Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2014.971358
2014, 1–7
Article ST-0318.R1/971358 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Review Autoimmune disorders in patients with hairy cell leukemia: are they more common than previously thought?
Constantin A. Dasanu Lucy Curci Cancer Center, Eisenhower Medical Center, Rancho Mirage, CA, USA
Magali Van den Bergh Donna Pepito Juliana Alvarez Argote Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT, USA Address for correspondence: Constantin A. Dasanu MD PhD, 131 Lake Shore Drive, Rancho Mirage, CA 92270, USA. Tel: +1 347 679 9455; [email protected] Keywords: Antiphospholipid antibody syndrome – Autoimmune disorders – Collagen vascular disorders – Hairy cell leukemia – Immune cytopenia – Vasculitis Accepted: 16 September 2014; published online: 17 October 2014 Citation: Curr Med Res Opin 2014; 1–7
Abstract Background: For a number of decades, hairy cell leukemia (HCL) has been linked with polyarthritis, vasculitis, symptomatic cytopenias and thrombosis in the medical literature. Notwithstanding, the significance of these associations has not been well understood. Therefore, we have decided to analyze them further. Methods: We provide herein a comprehensive literature review of the prevalence of autoimmune disorders in patients with HCL. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2014. Findings: Perhaps due to the rarity of HCL, scientific literature on autoimmune conditions in patients with HCL consists mainly of published case series and isolated reports. Our analysis identified increased prevalence of various autoimmune conditions in patients with HCL, including various vasculitides, immune cytopenias and antiphospholipid antibody syndrome (APS) among others. Conclusions: Presence of certain autoimmune disorders should increase the suspicion of HCL in an appropriate clinicolaboratory context. Conversely, the diagnosis of HCL should prompt early recognition of certain autoimmune disorders if clinical suspicion exists. While some of these autoimmune diseases are thought to be secondary to the dysfunctional immune response associated with underlying malignant process, others could be primary and might even play a role in the HCL pathogenesis. The autoimmune complications can pose important clinical problems for the HCL patients. Therefore, a catalogue of these problems is important for alerting physicians to watch for them and diagnose them promptly.
Introduction Hairy cell leukemia (HCL) is a rare clonal B-cell hematologic malignancy. Review of the literature suggests that HCL patients harbor impairments in both cellular and humoral mediated immunity1. Similarly to patients with other B-cell disorders, it appears that these patients also present an excess of autoimmune conditions1. Herein, we review the autoimmune abnormalities documented in the literature in patients with HCL. A systematic PubMed/ Medline review on hairy cell leukemia and autoimmune diseases was performed for articles published from inception to 28 February 2014. We searched Medline database for papers published in English using the term ‘hairy cell leukemia’ with each of the following keywords: ‘autoimmune’, ‘autoimmunity’, ‘autoimmune ! 2014 Informa UK Ltd www.cmrojournal.com
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
1
Current Medical Research & Opinion
2014
hemolytic anemia’, ‘immune thrombocytopenia’, ‘antiphospholipid syndrome’, ‘cryoglobulinemia’, ‘vasculitis’, ‘polyarthritis’, ‘scleroderma’, ‘polymyositis’, ‘autoimmune neuropathy’, ‘autoimmune nephropathy’ and ‘amyloidosis’. Articles were also obtained via cross-reference checking.
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Hairy cell leukemia: clinical features and diagnosis The overall incidence of HCL is estimated at 3.2 per million people per year in the United States. The median age of onset is 58 years, and it has a male-to-female ratio of approximately 4:1, affecting most notably Caucasian men. Risk factors include exposure to organic solvents, ionizing radiation, farming, pesticides, petroleum products, woodwork and sawdust2. In addition, genetic factors may play a role. Hairy cells, named after the visualization of hairy projections from the malignant B-cells under a microscope, are found in the peripheral blood, bone marrow and reticulo-endothelial system. The diagnosis of HCL is confirmed by increased reticulin fibrosis in the bone marrow (‘dry tap’), a positive tartrate resistant acid phosphatase (TRAP) stain, a specific immunophenotype on flow cytometry and by increased levels of soluble interleukin 2 surface receptors CD25 (solIL-2R) in the periphery2. HCL is usually characterized by splenomegaly and cytopenias, resulting in early satiety, fatigue, frequent infections and increased risk of bleeding. Pancytopenia is present in about half of patients, while the other half typically have a combination of two different cytopenias1. In cases where splenomegaly is present, hypersplenism is one of the mechanisms behind cytopenias. An absolute neutrophil count of 5500/mcl is seen in about 50% of the patients at the time of diagnosis of HCL1 and, only rarely, patients can present with leukocytosis2. Immunophenotypically, HCL is characterized by both conventional B-cell markers and specific markers including CD11c, CD25 and CD103. HCL patients present defects in both cellular and humoral-mediated immunity. Impaired cellular immunity pertains to alterations in natural killer cells, defective large granular lymphocytic cells, and decreased numbers of dendritic cells, monocytes and neutrophils1. Defective humoral immunity entails impairments in immunoglobulin production, synthesis of abnormal proteins and autoantibodies, as well as defective production and release of cytokines1. This immune dysregulation contributes to increased susceptibility to opportunistic infections2. Purine analogs such as cladribine and pentostatin are effective in treating this lymphoproliferative disorder and a high percentage of patients achieve sustained complete remissions. 2
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
Autoimmunity and hairy cell leukemia The coexistence of HCL and autoimmune phenomena has been documented in the literature as early as 1979. The first such reported cases linked polyarteritis nodosa and rheumatoid arthritis with HCL3. Over the last few decades, dozens of reports surfaced on both hematologic and nonhematologic autoimmune conditions in the setting of HCL. These autoimmune conditions can develop anytime during the course of HCL, although the majority are identified within the first year of diagnosis3. Although more than 25% of patients with HCL are thought to have at least one autoimmune condition4, the available literature is mostly limited to individual case reports and small series. The standard first-line treatment for HCL, cladribine, is highly effective in achieving and sustaining complete remissions. It also has some activity in progressive multiple sclerosis, autoimmune hemolytic anemia (AIHA), rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis and in patients with refractory factor VIII inhibitors5.
Autoimmune hematologic conditions Autoimmune hemolytic anemia (AIHA) has been known to be associated with different lymphoproliferative disorders. In 1992, Domingo et al.6 described the first case of AIHA with warm autoantibody associated with HCL (Table 1). The patient had increased numbers of CD8þ T-cells with concomitant depletion of CD4þ T-cells. The authors hypothesized that AIHA was either secondary to the HCL or a predisposing factor for its development. Mainwaring et al.7 reported two cases of fatal AIHA with cold (anti-i) autoantibody. The patients had no evidence of infectious mononucleosis, cytomegalovirus infection or acquired immune deficiency syndrome. Hemolysis in both cases was brisk and refractory to therapy. Notably, death as a consequence of AIHA with cold autoantibody is rare. The authors raise awareness that severe cold autoantibody AIHA may occur as a consequence of HCL. The mechanism for the occurrence of fatal AIHA with cold anti-i in HCL is thought to be similar to the one found in chronic lymphocytic leukemia (CLL)7. AIHA occurs in 10% of CLL and its pathophysiology has clearly been established. Red cell autoantibodies in CLL are thought to be secreted by polyclonal bystander B-cells (rather than the malignant clone itself) as a consequence of immune dysregulation in this disease8. Another potential explanation of AIHA in lymphoproliferative disorders relates to the autoimmune phenomena induced by nucleoside analog therapy that results in the loss of regulatory T-cells. However, the latter was unlikely the mechanism in the cases described as AIHA manifested itself prior to www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion
2014
Table 1. Hematologic autoimmune conditions associated with HCL. No. patients
Autoimmune condition
1 2 1 1 7 1
AIHA AIHA ITP PRCA APS Cryoglobulinemia
Characteristics
Reference
Warm autoantibody Cold autoantibodies; brisk hemolysis Absence of splenomegaly; HCL diagnosed after ITP Complete remission after rituximab therapy Rare but severe thrombotic events Frequent cutaneous and renal involvement
6 7 9 11 12 13
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
AIHA: autoimmune hemolytic anemia; ITP: immune thrombocytopenia; PRCA: pure red cell aplasia; APS: antiphospholipid syndrome.
Table 2. Rheumatologic autoimmune conditions associated with HCL. No. patients
Autoimmune condition
17 21 10 2 1 1 1 1
PAN LCV Arthritis PS Scleroderma Behcet’s disease Dermatomyositis SLE
Characteristics
Reference
PAN diagnosed after HCL, splenectomy and infection Often preceded by infection and diagnosed before HCL Acute, oligoarticular, asymmetrical Mimics rheumatoid arthritis; normal radiologic appearance; erosions seen less frequently In a male patient Marked improvement with steroids
14
SLE refractory to conventional therapy; improved after HCL therapy and splenectomy
31
14 19 23 26 28 29
PAN: polyarteritis nodosa; LCV: leukocytoclastic vasculitis; PS: proliferative synovitis; SLE: systemic lupus erythematosus.
initiation of HCL therapy. Furthermore, nucleoside analogs have been associated with the warm antibody type (anti-Rh) of AIHA. In 1998, Virchis et al.9 described a patient with HCL variant who presented with ITP. The interesting aspect of their case was the absence of splenomegaly, which likely reflected early stage disease. If not for the development of ITP in this case, HCL would have been diagnosed late. Ultimately, the patient accomplished a clinical and hematologic remission post-splenectomy9. Although uncommon, isolated neutropenia was described as initial presentation of HCL10. The diagnosis of HCL was based on characteristic cells present in bone marrow, and empiric treatment with recombinant human G-CSF was administered for neutropenia. Quach et al.11 described a case of pure red cell aplasia (PRCA) in a patient with HCL who subsequently achieved a complete remission with rituximab therapy. Patients with autoimmune cytopenias can present with mucosal bleeding, life-threatening infections and symptomatic anemia, respectively. G-CSF and increased transfusion requirements are oftentimes necessary. Diz-kucukkaya et al.12 described a case of antiphospholipid syndrome (APS) in a patient with HCL. Our literature review showed a total of seven such cases, all presenting with concomitant HCL and APS (Table 1). The pathogenesis may include autoantibody production in response to tumor antigens, secretion of phospholipids from affected tissues or monoclonal antibody production with antiphospholipid activity. Thrombotic complications ! 2014 Informa UK Ltd www.cmrojournal.com
are uncommon; however, when seen, they are extensive and include deep vein thromboses, pulmonary embolism and thromboses of cerebral vessels1. Raju et al.13 described the first case of cryoglobulinemia in the setting of HCL in 1984. HCL has been associated with type I cryoglobulinemia, which has a more severe clinical presentation due to frequent cutaneous and renal involvement.
Rheumatologic diseases Panarteritis nodosa (PAN), cutaneous leukocytoclastic vasculitis (LCV) and giant cell arteritis (GCA) have all been linked to HCL14–17 (Table 2). The development of vasculitis can occur at any time during the course of HCL, but tends to occur rather earlier than later. Symptoms include but are not limited to fever, arthralgia, erythema nodosum, other skin lesions and peripheral neuropathy2. Hasler et al.14 reported a series of 42 patients with vasculitis in patients with HCL; 17 of them had PAN, 21 had LCV and four demonstrated vessel wall infiltration with hairy cells. Infiltration of the vessel wall by the hairy cells occurred after the diagnosis of HCL was made. Direct injury to the endothelium and intima by infiltrating cells and local production of cytokines and antibodies are the postulated mechanisms mediating tissue injury. For the most part, PAN occurred after HCL and splenectomy, and was often preceded by infection. Significant infection may lead to an increase in circulating immune complexes Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
3
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
2014
caused by impaired reticuloendothelial system function or splenectomy. The theory of antibody cross-reactivity that targets surface determinants on hairy cells as well as epitopes on the endothelial cells could explain the occurrence of vasculitis14,16,18. The first case of PAN in the context of HCL was described by Hughes et al. in 197915. PAN may be difficult to distinguish from HCL-related vasculitis. However, involvement of temporal and cerebral arteries is atypical for PAN and would suggest GCA or another entity17. Westbrook et al.19 retrospectively reviewed the records of 37 patients with HCL for the evidence of autoimmune disease. Arthritis was identified in 10 patients, and they had two different arthritic presentations. Six patients had arthralgias, arthritis and nodular skin lesions. The arthritis was acute, oligoarticular and usually affected the knees, elbows and shoulders. This type of arthritis in HCL may be due to leukemic infiltration or immune-mediated inflammation19. The second variant (4/10 patients) was diagnosed prior to or after the clinical onset of HCL, and had a clinical presentation similar to rheumatoid arthritis, systemic lupus or scleroderma20. Ehrlich et al.21 reported the simultaneous occurrence of acute palindromic rheumatism and leukemia in 1934. Arthralgia and joint swelling are recognized features of acute leukemia; however, migratory polyarthritis is most commonly seen in leukemia-associated arthritis. It is oftentimes polyarticular, asymmetrical and usually occurs at the initial manifestation of the disease. Rheumatism in HCL usually affects the ankles, knees and shoulders. The cause of arthritis in HCL is attributed to leukemic infiltrates in the metaphyseal periosteum and articular cavities, periarticular hemorrhages and/or synovial membrane leukemic infiltrates22. Immune complex mediated processes resulting in proliferative synovitis are mostly seen in T-cell leukemia, but have also been described in HCL23. Joint involvement is usually symmetrical and mimics rheumatoid arthritis clinically. Radiographically, the joints tend to appear normal, and erosions are seen less often. The pathogenic mechanism that leads to proliferative synovitis in HCL is not yet clarified. Scleroderma has been reported in several patients with HCL. Blanche et al.24 define ‘paraneoplastic scleroderma’ as scleroderma presenting in close temporal relationship to malignancy, scleroderma following the progression of malignancy or a severe, rapidly progressing scleroderma in patients with malignancy. Some case series report atypical features such as the absence of hallmark autoantibodies or disproportionate palmar fibrosis in scleroderma occurring in HCL patients25. Nonetheless, Juarez et al.26 presented a case demonstrating clinical and laboratory features very similar to idiopathic scleroderma. The unusual feature in their case was the male gender as 80% of scleroderma patients are female. The immune system 4
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
abnormalities are thought to influence the relationship between scleroderma and HCL. At the molecular level, fibronectin and cytokines such as fibroblast growth factor and TGF-b, which are products of HCL cells, are responsible for bone marrow fibrosis, while another product, TNF-a, causes bone marrow suppression. The effector cells causing fibrotic changes in scleroderma are activated fibroblasts. TGF-b is the key driver of scleroderma as it promotes extracellular matrix synthesis and myofibroblast differentiation and, interestingly, is produced excessively in HCL. It has been speculated that the two conditions have a common pathogenesis. Cladribine, which has cytotoxic effects in both proliferating and quiescent hairy cells, was also shown to halt scleroderma progression25–27. Oo et al.28 presented a patient with untreated HCL who later on developed Behc¸et’s disease. The complex immunologic imbalance was believed to be the common denominator, which led to the manifestation of both conditions. Prednisone therapy resulted in marked improvement of Behc¸et’s disease, while patient’s HCL remained stable. Marie et al.29 described a series of 32 patients with hematologic malignancies, five of which had concurrent polymyositis (PM) or dermatomyositis (DM). One of the five patients had HCL and DM. The myositis in hematologic malignancies is thought to be caused by the altered immune system, which leads to muscle destruction, and the inability to suppress the neoplastic cell proliferation. In patients with DM associated with a hematologic malignancy, tumor antigens are thought to trigger the autoimmune process by endothelial antigen mimicry or by-stander stimulation. Conversely, the chronic immune stimulation seen in patients with PM/DM has also been suggested to cause T-cell and B-cell activation, which in turn may lead to malignant lymphocyte transformation30. Systemic lupus erythematosus (SLE) has also been reported in patients with HCL31,32. Strickland et al.31 described a young Hispanic man presenting with a typical SLE flare that was refractory to therapy (Table 2). Due to striking leukopenia, a bone marrow biopsy was performed and yielded the diagnosis of HCL. Notably, leukopenia occurs in greater than 50% of SLE patients with white blood cell count usually greater than 2000 cells/mm3, while only less than 4% have severe leukopenia. This led to the suspicion of another underlying pathology despite a classic SLE presentation. Complete resolution of rheumatic symptoms was accomplished once splenectomy and pharmacotherapy for HCL were initiated31.
Autoimmune neurologic disorders Reports in the literature described autoimmune neurologic conditions including myasthenia gravis (MG) and multiple sclerosis (MS) in patients with HCL33,34. In the www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion
2014
Table 3. Miscellaneous autoimmune conditions associated with HCL. No. patients
Autoimmune condition
1 1 1 1 1
Multiple sclerosis Nephrotic syndrome UC AL amyloidosis AA amyloidosis
Characteristics
Reference
Good response to cladribine Immune mediated GN and cryoglobulinemia UC diagnosed in the setting of HCL treated with IFN-alpha Amyloidosis diagnosed after HCL Amyloidosis diagnosed after HCL
34 36 37 38 39
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
GN: glomerulonephritis; UC: ulcerative colitis; AL: amyloid light chain; AA: amyloid protein A.
reported case, MG preceded HCL33. HCL was also described in a patient with longstanding MS34. Both HCL and MS went on to respond to cladribine therapy (Table 3). As this is the only such case report in the literature, the relationship between HCL and MS remains to be further explored.
Other autoimmune conditions Membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy were described in patients with CLL, non-Hodgkins lymphoma and HCL. MPGN in HCL is thought to be caused by the monoclonal immunoglobulin secreted by the B-cell clone35. Douglas et al.36 described a patient with nephrotic syndrome and HCL who was diagnosed with immune-mediated glomerulonephritis and cryoglobulinemia (Table 3). Pecorari37 reported a case of ulcerative colitis (UC) in a patient treated with interferon-alpha for HCL. The suggested mechanism for this occurrence was thought to be the imbalance between T-helper 1 and T-helper 2 cells as T-helper 2 cell excess is often seen in patients with UC. Both AL and AA amyloidosis were described in patients with HCL (Table 3)38,39. A clonal B-lymphocyte disorder, HCL is associated with systemic monoclonal immunoglobulin light chain production, which is also a requirement for the development of amyloid light-chain (AL) amyloidosis. It is not entirely clear however whether proliferating hairy cells are monoclonal with respect to Ig light chain type, while AL amyloidosis requires the presence of a monoclonal gammopathy38. AA proteins are characteristic deposits in secondary amyloidosis and are thought to be related to the chronic inflammatory state seen in HCL39. Interestingly, AA amyloidosis is not uncommonly seen with various collagen vascular disorders, known to be associated with HCL as well.
Discussion Since 1970s–80s, HCL has been associated with vasculitis, polyarthritis and thrombosis in an important number of patients. Given the fact that the above associations have ! 2014 Informa UK Ltd www.cmrojournal.com
lingered over half a century, we decided to analyze them further. HCL has been associated with different rheumatologic diseases such as PAN, LCV and GCA, which are known to have an autoimmune basis. Leading to blood vessel injury, these conditions tend to occur rather earlier than later in the course of HCL, and may be difficult to distinguish from HCL-related vasculitis. Arthritic syndromes similar to the ones in rheumatoid arthritis, systemic lupus or scleroderma have been described in patients with HCL. Joint involvement is usually symmetrical and most often mimics clinically rheumatoid arthritis; however, asymmetrical arthritis can also be seen in these patients. Used for the HCL therapy, cladribine was shown to arrest symptoms of both scleroderma and systemic lupus in several reports. PM and DM were also described in patients with HCL, and they presented at the diagnosis of HCL. Autoimmune blood disorders associated with HCL include various autoimmune cytopenias. AIHA is the most common cytopenia associated with HCL. The most prevalent type is the cold (anti-i) autoantibody AIHA that can be severe and even fatal. Other cytopenias associated with HCL include ITP, autoimmune neutropenia and PRCA. APS is an autoimmune thrombotic disorder associated with HCL, and usually presents at the diagnosis of HCL. APS seen in HCL can be primary or secondary to a collagen vascular disorder such as systemic lupus or rheumatoid arthritis. Antibody-mediated neuro-endocrine diseases are less common than autoimmune hematologic or rheumatologic conditions in patients with HCL. Rare reports of immune-mediated glomerulonephritis and cryoglobulinemia have also surfaced in patients with HCL. A large case–control study published by Anderson and Engels40 compared 418 cases of HCL with 160,086 controls and concluded that there was no overall increased prevalence of autoimmune conditions in patients with HCL. However, their study did in fact show increased prevalence of certain autoimmune conditions in HCL, namely ankylosing spondylitis (odds ratio [OR] 12.2, CI 1.7–90), erythema nodosum (OR 37, CI 4.9–284), Hashymoto thyroiditis (OR 10.3 CI 2.5–42.3), SLE (OR 7.2 CI 2.3–22.8), pernicious anemia (OR 3.4 CI 1.6–7.1), sarcoidosis (OR 9.6 CI 2.4–39.5) and Sjogren syndrome (OR 7.9 CI 1.1–57.5). Notably, these conditions were Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
5
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
2014
identified either prior to or at the moment of HCL diagnosis, but none thereafter. We also believe that some confounding variables in that study could have influenced the results. For instance, the control group included more female patients when compared to the HCL cohort (51% vs. 32%), which could have falsely increased the incidence of autoimmune disorders since women are at higher risk than men in that regard41. In addition, the study only included patients aged 67–99 but not younger which could have otherwise yielded different results. Furthermore, the control group included patients that were relatively younger than the HCL patients (46% vs. 37% patients were aged 67–74), and studies have shown the prevalence of autoimmune diseases to be higher in the 65–75 age group as opposed to subjects 75–85 years or older41. This could have shown a higher prevalence of autoimmune conditions in the control group compared with HCL group, leading to a type 2 error. Unfortunately, available literature on autoimmune conditions in HCL consists of mainly retrospective analyses of case series and isolated reports. This represents the weakness of our study as overgeneralizations may occur in this context. Retrospective design of the included case series may also limit the accuracy of our analysis. In addition, conclusions of the present study might render an overestimation of the association between autoimmune conditions and HCL. Furthermore, the possibility of publication bias is a valid concern for any synthetic and/or analytic reviews. It reflects the reality that studies reporting positive associations are more likely to be published than the ones reporting negative associations. Exclusion of studies published in other languages than English from the current systematic analysis might represent another potential source of publication bias. Finally, some associations between instances of autoimmunity and HCL could represent a mere coincidence as they may not be interrelated. Nonetheless, many of the published studies suggest potential common steps in the pathogenesis for both autoimmune conditions and HCL as these conditions more often than not present concurrently with HCL and tend to respond to the therapy with nucleoside analogs. Yet, the exact steps of pathogenesis underlying these disorders remain to be discovered. Close surveillance including regular follow-up could be important as early detection of autoimmune conditions may improve clinical outcomes in patients with HCL. Conversely, diagnosis of an autoimmune disease could lead to the HCL diagnosis as many autoimmune diseases present early in its course or may even precede HCL. However, due to lack of solid data, there are no specific guidelines in terms of optimal screening for autoimmunity in patients with HCL. Certainly, further studies including prospective data and cost–benefit analysis of intensive screening are warranted, and could help establish new guidelines for management of HCL patients. 6
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
Conclusions Patients with HCL present intricate immune alterations and an excess of autoimmune conditions. Autoimmune disorders can develop prior to, during or after the onset of HCL. Some of them could be secondary to the dysfunctional immune response associated with the underlying malignant process, while others might be primary and play a role in the HCL pathogenesis. In caring for patients with this rare chronic form of leukemia, many autoimmune complications are recognized. Knowing these manifestations is important not only for making a correct diagnosis at the patient’s initial presentation, but also for evaluating clinical events occurring during the course of the disease. There is a variety of clinical manifestations that do not always present in the identical manner, thus making recognition difficult. The rare nature and limited number of patients seen in any one center in a defined timeframe also complicate recognition and description of these disorders. The autoimmune complications can pose significant clinical problems for the HCL patients and their providers. Therefore, a catalog of these problems in HCL is important for alerting physicians to watch for them.
Transparency Declaration of funding This review was not funded. Declaration of financial/other relationships M.V.d.B., D.P., and J.A.-A. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. C.A.D. has disclosed that he is a member of CMRO’s Editorial Board but has no relevant financial or other relationships to disclose. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. Dasanu CA, Ichim TE, Alexandrescu DT. Inherent and iatrogenic immune defects in hairy cell leukemia: revisited. Expert Opin Drug Saf 2010;9:55-64 2. Polliack A. Hairy cell leukemia: biology, clinical diagnosis, unusual manifestations and associated disorders. Rev Clin Exp Hematol 2002;6:366-88 3. Tadmor T, Polliack A. Unusual clinical manifestations, rare sites of involvement, and the association of other disorders with hairy cell leukemia. Leuk Lymphoma 2011;52(Suppl 2):57-61 4. Kraut E. Clinical manifestations and infectious complications of hairy-cell leukemia. Best Pract Res Clin Haematol 2003;16:33-40 5. Robak T. Recent clinical trials of cladribine in hematologic malignancies and autoimmune disorders. Rev Recent Clin Trials 2006;1:15-34 6. Domingo A, Crespo N, Fernandez de Sevilla A, et al. Hairy cell leukemia and autoimmune hemolytic anemia. Leukemia 1992;6:606-7 7. Mainwaring CJ, Walewska R, Snowden J, et al. Fatal cold anti-I autoimmune hemolytic anaemia complicating hairy cell leukemia. Br J Haematol 2000;109:641-3
www.cmrojournal.com ! 2014 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
8. Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood 1993;81:2475-87 9. Virchis AE, Jan-Mohamed R, Kaczmarski KS, et al. Primary splenic hairy cell leukemia variant presenting as immune thrombocytopenic purpura. Eur J Haematol 1998;61:288-91 10. Diop S, Ndiaye MF, Farah F, et al. Hairy cell leukemia revealed by an isolated neutropenia. Dakar Med 2003;48:230-2 11. Quach H, Januszewicz H, Westerman D. Complete remission of hairy cell leukemia variant (HCL-v) complicated by red cell aplasia post treatment with rituximab. Haematologica 2005;90(Suppl):ECR26 12. Diz-kucukkaya R, Dincol G, Kamali S, et al. Development of hairy cell leukemia in a patient with antiphospholipid syndrome. Lupus 2007;16:286-8 13. Raju SF, Chapman SW, Dreiling B, et al. Hairy-cell leukemia with the appearance of mixed cryoglobulinemia and vasculitis. Arch Intern Med 1984;144:1300-2 14. Hasler P, Kistler H, Gerber H. Vasculitides in hairy cell leukemia. Semin Arthritis Rheum 1995;25:134-42 15. Hughes GR, Elkon KB, Spiller R, et al. Polyarteritis nodosa and hairy-cell leukaemia. Lancet 1979;1:678 16. Farcet JP, Weschsler J, Wirquin V, et al. Vasculitis in hairy cell leukemia. Arch Intern Med 1987;147:660-4 17. Fortin PR. Vasculitides associated with malignancy. Curr Opin Rheumatol 1996;8:30-3 18. Gabriel SE, Conn DL, Phyliky RL, et al. Vasculitis in hairy cell leukemia: review of literature and consideration of possible pathogenic mechanisms. J Rheumatol 1986;13:1167-72 19. Westbrook CA, Golde DW. Autoimmune disease in hairy-cell leukaemia: clinical syndromes and treatment. Br J Haematol 1985;61:349-56 20. Vernhes JP, Schaeverbeke T, Fach J, et al. Chronic immunity-driven polyarthritis in hairy cell leukemia. Report of a case and review of the literature. Rev Rhum Engl Ed 1997;64:578-81 21. Ehrlich J, Forer S. Periosteal ossification in Myelogenous leukemia. Arch Intern Med (Chic) 1934;53:938-52 22. Sattar MA, Cawley MI. Arthritis associated with hairy cell leukaemia. Ann Rheum Dis 1982;41:289-91 23. Zervas J, Vayopoulos G, Kaklamanis PH, et al. Hairy cell leukemia-associated polyarthritis. A report of two cases. Br J Rheumatol 1991;30:157-8 24. Blanche P, Bachmeyer C, Mikdame M, et al. Scleroderma, polymyositis and hairy cell leukemia. J Rheumatol 1995;22:1384-5 25. Naschitz JE, Rosner I, Rozenbaum M, et al. Rheumatic syndromes: clues to occult neoplasia. Semin Arthritis Rheum 1999;29:43-55
! 2014 Informa UK Ltd www.cmrojournal.com
2014
26. Juarez M, Marshall R, Denton C, et al. Paraneoplastic scleroderma secondary to hairy cell leukaemia successfully treated with cladribine. Rheumatology (Oxford) 2008;47:1734-5 27. Dasanu CA, Stoica-Mustafa E, Herlea V, et al. New therapies for patients with hairy cell leukemia at a glance: comprehensive review article with an illustrative case. Ann Fundeni Hosp 2005;10:75-8 28. Oo T, Delafuente M, Hassoun H. Possible association between hairy cell leukemia and Behc¸et’s disease. South Med J 2003;96:323-4 29. Marie I, Guillevin J, Menard JF, et al. Hematologic malignancy associated with polymyositis and dermatomyositis. Autoimmun Rev 2012;11:615-20 30. Zampieri S, Valente M, Adami N, et al. Polymyositis, dermatomyositis and malignancy: a further intriguing link. Autoimmun Rev 2010;9: 449-53 31. Strickland R, Limmani A, Wall JG, et al. Hairy cell leukemia presenting as lupus-like illness. Arthritis Rheum 1988;31:566-8 32. Harvey AM, Shulman LE, Tumulty PA, et al. Systemic lupus erythematosis: review of literature and clinical analysis of 138 cases. Medicine (Baltimore) 1954;33:291-437 33. Garcia-Giron C, Ferna´ndez de Castro M, Jime´nez Herra´ez C, et al. The association of myasthenia gravis and hairy cell leukemia. Med Clin (Barc) 1991;97:703-5 34. Hilbe W, Berger T, Konwalinka G, et al. Cladribine treatment of a patient with hairy cell leukemia and concomitant multiple sclerosis. Acta Haematol 1999;102:99-100 35. Favre G, Courtellemont C, Callard P, et al. Membranoproliferative glomerulonephritis, chronic lymphocytic leukemia, and cryoglobulinemia. Am J Kidney Dis 2010;55:391-4 36. Douglas MF, Schwartz MM, Sharon Z. Cryoglobulinemia and immunemediated glomerulonephritis in association with hairy cell leukemia. Am J Kidney Dis 1985;6:181-4 37. Pecorari P. Ulcerative colitis in hairy cell leukemia. A case report. Recenti Prog Med 1991;82:269-71 38. Benson MD, Kramer G, Abonour R. Hairy cell leukemia and light chain (AL) amyloidosis: a case report. Amyloid 2011;18(Suppl 1):101-2 39. Linder J, Silberman HR, Croker BP. Amyloidosis complicating hairy cell leukemia. Am J Clin Pathol 1982;78:864-7 40. Anderson LA, Engels EA. Autoimmune conditions and hairy cell leukemia: an exploratory case–control study. J Hematol Oncol 2010;3:35 41. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adultonset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63:633-9
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
7
2014, 1–7
Article ST-0318.R1/971358 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Review Autoimmune disorders in patients with hairy cell leukemia: are they more common than previously thought?
Constantin A. Dasanu Lucy Curci Cancer Center, Eisenhower Medical Center, Rancho Mirage, CA, USA
Magali Van den Bergh Donna Pepito Juliana Alvarez Argote Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT, USA Address for correspondence: Constantin A. Dasanu MD PhD, 131 Lake Shore Drive, Rancho Mirage, CA 92270, USA. Tel: +1 347 679 9455; [email protected] Keywords: Antiphospholipid antibody syndrome – Autoimmune disorders – Collagen vascular disorders – Hairy cell leukemia – Immune cytopenia – Vasculitis Accepted: 16 September 2014; published online: 17 October 2014 Citation: Curr Med Res Opin 2014; 1–7
Abstract Background: For a number of decades, hairy cell leukemia (HCL) has been linked with polyarthritis, vasculitis, symptomatic cytopenias and thrombosis in the medical literature. Notwithstanding, the significance of these associations has not been well understood. Therefore, we have decided to analyze them further. Methods: We provide herein a comprehensive literature review of the prevalence of autoimmune disorders in patients with HCL. Most relevant publications were identified through searching the PubMed/Medline database for articles published from inception to February 2014. Findings: Perhaps due to the rarity of HCL, scientific literature on autoimmune conditions in patients with HCL consists mainly of published case series and isolated reports. Our analysis identified increased prevalence of various autoimmune conditions in patients with HCL, including various vasculitides, immune cytopenias and antiphospholipid antibody syndrome (APS) among others. Conclusions: Presence of certain autoimmune disorders should increase the suspicion of HCL in an appropriate clinicolaboratory context. Conversely, the diagnosis of HCL should prompt early recognition of certain autoimmune disorders if clinical suspicion exists. While some of these autoimmune diseases are thought to be secondary to the dysfunctional immune response associated with underlying malignant process, others could be primary and might even play a role in the HCL pathogenesis. The autoimmune complications can pose important clinical problems for the HCL patients. Therefore, a catalogue of these problems is important for alerting physicians to watch for them and diagnose them promptly.
Introduction Hairy cell leukemia (HCL) is a rare clonal B-cell hematologic malignancy. Review of the literature suggests that HCL patients harbor impairments in both cellular and humoral mediated immunity1. Similarly to patients with other B-cell disorders, it appears that these patients also present an excess of autoimmune conditions1. Herein, we review the autoimmune abnormalities documented in the literature in patients with HCL. A systematic PubMed/ Medline review on hairy cell leukemia and autoimmune diseases was performed for articles published from inception to 28 February 2014. We searched Medline database for papers published in English using the term ‘hairy cell leukemia’ with each of the following keywords: ‘autoimmune’, ‘autoimmunity’, ‘autoimmune ! 2014 Informa UK Ltd www.cmrojournal.com
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
1
Current Medical Research & Opinion
2014
hemolytic anemia’, ‘immune thrombocytopenia’, ‘antiphospholipid syndrome’, ‘cryoglobulinemia’, ‘vasculitis’, ‘polyarthritis’, ‘scleroderma’, ‘polymyositis’, ‘autoimmune neuropathy’, ‘autoimmune nephropathy’ and ‘amyloidosis’. Articles were also obtained via cross-reference checking.
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Hairy cell leukemia: clinical features and diagnosis The overall incidence of HCL is estimated at 3.2 per million people per year in the United States. The median age of onset is 58 years, and it has a male-to-female ratio of approximately 4:1, affecting most notably Caucasian men. Risk factors include exposure to organic solvents, ionizing radiation, farming, pesticides, petroleum products, woodwork and sawdust2. In addition, genetic factors may play a role. Hairy cells, named after the visualization of hairy projections from the malignant B-cells under a microscope, are found in the peripheral blood, bone marrow and reticulo-endothelial system. The diagnosis of HCL is confirmed by increased reticulin fibrosis in the bone marrow (‘dry tap’), a positive tartrate resistant acid phosphatase (TRAP) stain, a specific immunophenotype on flow cytometry and by increased levels of soluble interleukin 2 surface receptors CD25 (solIL-2R) in the periphery2. HCL is usually characterized by splenomegaly and cytopenias, resulting in early satiety, fatigue, frequent infections and increased risk of bleeding. Pancytopenia is present in about half of patients, while the other half typically have a combination of two different cytopenias1. In cases where splenomegaly is present, hypersplenism is one of the mechanisms behind cytopenias. An absolute neutrophil count of 5500/mcl is seen in about 50% of the patients at the time of diagnosis of HCL1 and, only rarely, patients can present with leukocytosis2. Immunophenotypically, HCL is characterized by both conventional B-cell markers and specific markers including CD11c, CD25 and CD103. HCL patients present defects in both cellular and humoral-mediated immunity. Impaired cellular immunity pertains to alterations in natural killer cells, defective large granular lymphocytic cells, and decreased numbers of dendritic cells, monocytes and neutrophils1. Defective humoral immunity entails impairments in immunoglobulin production, synthesis of abnormal proteins and autoantibodies, as well as defective production and release of cytokines1. This immune dysregulation contributes to increased susceptibility to opportunistic infections2. Purine analogs such as cladribine and pentostatin are effective in treating this lymphoproliferative disorder and a high percentage of patients achieve sustained complete remissions. 2
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
Autoimmunity and hairy cell leukemia The coexistence of HCL and autoimmune phenomena has been documented in the literature as early as 1979. The first such reported cases linked polyarteritis nodosa and rheumatoid arthritis with HCL3. Over the last few decades, dozens of reports surfaced on both hematologic and nonhematologic autoimmune conditions in the setting of HCL. These autoimmune conditions can develop anytime during the course of HCL, although the majority are identified within the first year of diagnosis3. Although more than 25% of patients with HCL are thought to have at least one autoimmune condition4, the available literature is mostly limited to individual case reports and small series. The standard first-line treatment for HCL, cladribine, is highly effective in achieving and sustaining complete remissions. It also has some activity in progressive multiple sclerosis, autoimmune hemolytic anemia (AIHA), rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis and in patients with refractory factor VIII inhibitors5.
Autoimmune hematologic conditions Autoimmune hemolytic anemia (AIHA) has been known to be associated with different lymphoproliferative disorders. In 1992, Domingo et al.6 described the first case of AIHA with warm autoantibody associated with HCL (Table 1). The patient had increased numbers of CD8þ T-cells with concomitant depletion of CD4þ T-cells. The authors hypothesized that AIHA was either secondary to the HCL or a predisposing factor for its development. Mainwaring et al.7 reported two cases of fatal AIHA with cold (anti-i) autoantibody. The patients had no evidence of infectious mononucleosis, cytomegalovirus infection or acquired immune deficiency syndrome. Hemolysis in both cases was brisk and refractory to therapy. Notably, death as a consequence of AIHA with cold autoantibody is rare. The authors raise awareness that severe cold autoantibody AIHA may occur as a consequence of HCL. The mechanism for the occurrence of fatal AIHA with cold anti-i in HCL is thought to be similar to the one found in chronic lymphocytic leukemia (CLL)7. AIHA occurs in 10% of CLL and its pathophysiology has clearly been established. Red cell autoantibodies in CLL are thought to be secreted by polyclonal bystander B-cells (rather than the malignant clone itself) as a consequence of immune dysregulation in this disease8. Another potential explanation of AIHA in lymphoproliferative disorders relates to the autoimmune phenomena induced by nucleoside analog therapy that results in the loss of regulatory T-cells. However, the latter was unlikely the mechanism in the cases described as AIHA manifested itself prior to www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion
2014
Table 1. Hematologic autoimmune conditions associated with HCL. No. patients
Autoimmune condition
1 2 1 1 7 1
AIHA AIHA ITP PRCA APS Cryoglobulinemia
Characteristics
Reference
Warm autoantibody Cold autoantibodies; brisk hemolysis Absence of splenomegaly; HCL diagnosed after ITP Complete remission after rituximab therapy Rare but severe thrombotic events Frequent cutaneous and renal involvement
6 7 9 11 12 13
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
AIHA: autoimmune hemolytic anemia; ITP: immune thrombocytopenia; PRCA: pure red cell aplasia; APS: antiphospholipid syndrome.
Table 2. Rheumatologic autoimmune conditions associated with HCL. No. patients
Autoimmune condition
17 21 10 2 1 1 1 1
PAN LCV Arthritis PS Scleroderma Behcet’s disease Dermatomyositis SLE
Characteristics
Reference
PAN diagnosed after HCL, splenectomy and infection Often preceded by infection and diagnosed before HCL Acute, oligoarticular, asymmetrical Mimics rheumatoid arthritis; normal radiologic appearance; erosions seen less frequently In a male patient Marked improvement with steroids
14
SLE refractory to conventional therapy; improved after HCL therapy and splenectomy
31
14 19 23 26 28 29
PAN: polyarteritis nodosa; LCV: leukocytoclastic vasculitis; PS: proliferative synovitis; SLE: systemic lupus erythematosus.
initiation of HCL therapy. Furthermore, nucleoside analogs have been associated with the warm antibody type (anti-Rh) of AIHA. In 1998, Virchis et al.9 described a patient with HCL variant who presented with ITP. The interesting aspect of their case was the absence of splenomegaly, which likely reflected early stage disease. If not for the development of ITP in this case, HCL would have been diagnosed late. Ultimately, the patient accomplished a clinical and hematologic remission post-splenectomy9. Although uncommon, isolated neutropenia was described as initial presentation of HCL10. The diagnosis of HCL was based on characteristic cells present in bone marrow, and empiric treatment with recombinant human G-CSF was administered for neutropenia. Quach et al.11 described a case of pure red cell aplasia (PRCA) in a patient with HCL who subsequently achieved a complete remission with rituximab therapy. Patients with autoimmune cytopenias can present with mucosal bleeding, life-threatening infections and symptomatic anemia, respectively. G-CSF and increased transfusion requirements are oftentimes necessary. Diz-kucukkaya et al.12 described a case of antiphospholipid syndrome (APS) in a patient with HCL. Our literature review showed a total of seven such cases, all presenting with concomitant HCL and APS (Table 1). The pathogenesis may include autoantibody production in response to tumor antigens, secretion of phospholipids from affected tissues or monoclonal antibody production with antiphospholipid activity. Thrombotic complications ! 2014 Informa UK Ltd www.cmrojournal.com
are uncommon; however, when seen, they are extensive and include deep vein thromboses, pulmonary embolism and thromboses of cerebral vessels1. Raju et al.13 described the first case of cryoglobulinemia in the setting of HCL in 1984. HCL has been associated with type I cryoglobulinemia, which has a more severe clinical presentation due to frequent cutaneous and renal involvement.
Rheumatologic diseases Panarteritis nodosa (PAN), cutaneous leukocytoclastic vasculitis (LCV) and giant cell arteritis (GCA) have all been linked to HCL14–17 (Table 2). The development of vasculitis can occur at any time during the course of HCL, but tends to occur rather earlier than later. Symptoms include but are not limited to fever, arthralgia, erythema nodosum, other skin lesions and peripheral neuropathy2. Hasler et al.14 reported a series of 42 patients with vasculitis in patients with HCL; 17 of them had PAN, 21 had LCV and four demonstrated vessel wall infiltration with hairy cells. Infiltration of the vessel wall by the hairy cells occurred after the diagnosis of HCL was made. Direct injury to the endothelium and intima by infiltrating cells and local production of cytokines and antibodies are the postulated mechanisms mediating tissue injury. For the most part, PAN occurred after HCL and splenectomy, and was often preceded by infection. Significant infection may lead to an increase in circulating immune complexes Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
3
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
2014
caused by impaired reticuloendothelial system function or splenectomy. The theory of antibody cross-reactivity that targets surface determinants on hairy cells as well as epitopes on the endothelial cells could explain the occurrence of vasculitis14,16,18. The first case of PAN in the context of HCL was described by Hughes et al. in 197915. PAN may be difficult to distinguish from HCL-related vasculitis. However, involvement of temporal and cerebral arteries is atypical for PAN and would suggest GCA or another entity17. Westbrook et al.19 retrospectively reviewed the records of 37 patients with HCL for the evidence of autoimmune disease. Arthritis was identified in 10 patients, and they had two different arthritic presentations. Six patients had arthralgias, arthritis and nodular skin lesions. The arthritis was acute, oligoarticular and usually affected the knees, elbows and shoulders. This type of arthritis in HCL may be due to leukemic infiltration or immune-mediated inflammation19. The second variant (4/10 patients) was diagnosed prior to or after the clinical onset of HCL, and had a clinical presentation similar to rheumatoid arthritis, systemic lupus or scleroderma20. Ehrlich et al.21 reported the simultaneous occurrence of acute palindromic rheumatism and leukemia in 1934. Arthralgia and joint swelling are recognized features of acute leukemia; however, migratory polyarthritis is most commonly seen in leukemia-associated arthritis. It is oftentimes polyarticular, asymmetrical and usually occurs at the initial manifestation of the disease. Rheumatism in HCL usually affects the ankles, knees and shoulders. The cause of arthritis in HCL is attributed to leukemic infiltrates in the metaphyseal periosteum and articular cavities, periarticular hemorrhages and/or synovial membrane leukemic infiltrates22. Immune complex mediated processes resulting in proliferative synovitis are mostly seen in T-cell leukemia, but have also been described in HCL23. Joint involvement is usually symmetrical and mimics rheumatoid arthritis clinically. Radiographically, the joints tend to appear normal, and erosions are seen less often. The pathogenic mechanism that leads to proliferative synovitis in HCL is not yet clarified. Scleroderma has been reported in several patients with HCL. Blanche et al.24 define ‘paraneoplastic scleroderma’ as scleroderma presenting in close temporal relationship to malignancy, scleroderma following the progression of malignancy or a severe, rapidly progressing scleroderma in patients with malignancy. Some case series report atypical features such as the absence of hallmark autoantibodies or disproportionate palmar fibrosis in scleroderma occurring in HCL patients25. Nonetheless, Juarez et al.26 presented a case demonstrating clinical and laboratory features very similar to idiopathic scleroderma. The unusual feature in their case was the male gender as 80% of scleroderma patients are female. The immune system 4
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
abnormalities are thought to influence the relationship between scleroderma and HCL. At the molecular level, fibronectin and cytokines such as fibroblast growth factor and TGF-b, which are products of HCL cells, are responsible for bone marrow fibrosis, while another product, TNF-a, causes bone marrow suppression. The effector cells causing fibrotic changes in scleroderma are activated fibroblasts. TGF-b is the key driver of scleroderma as it promotes extracellular matrix synthesis and myofibroblast differentiation and, interestingly, is produced excessively in HCL. It has been speculated that the two conditions have a common pathogenesis. Cladribine, which has cytotoxic effects in both proliferating and quiescent hairy cells, was also shown to halt scleroderma progression25–27. Oo et al.28 presented a patient with untreated HCL who later on developed Behc¸et’s disease. The complex immunologic imbalance was believed to be the common denominator, which led to the manifestation of both conditions. Prednisone therapy resulted in marked improvement of Behc¸et’s disease, while patient’s HCL remained stable. Marie et al.29 described a series of 32 patients with hematologic malignancies, five of which had concurrent polymyositis (PM) or dermatomyositis (DM). One of the five patients had HCL and DM. The myositis in hematologic malignancies is thought to be caused by the altered immune system, which leads to muscle destruction, and the inability to suppress the neoplastic cell proliferation. In patients with DM associated with a hematologic malignancy, tumor antigens are thought to trigger the autoimmune process by endothelial antigen mimicry or by-stander stimulation. Conversely, the chronic immune stimulation seen in patients with PM/DM has also been suggested to cause T-cell and B-cell activation, which in turn may lead to malignant lymphocyte transformation30. Systemic lupus erythematosus (SLE) has also been reported in patients with HCL31,32. Strickland et al.31 described a young Hispanic man presenting with a typical SLE flare that was refractory to therapy (Table 2). Due to striking leukopenia, a bone marrow biopsy was performed and yielded the diagnosis of HCL. Notably, leukopenia occurs in greater than 50% of SLE patients with white blood cell count usually greater than 2000 cells/mm3, while only less than 4% have severe leukopenia. This led to the suspicion of another underlying pathology despite a classic SLE presentation. Complete resolution of rheumatic symptoms was accomplished once splenectomy and pharmacotherapy for HCL were initiated31.
Autoimmune neurologic disorders Reports in the literature described autoimmune neurologic conditions including myasthenia gravis (MG) and multiple sclerosis (MS) in patients with HCL33,34. In the www.cmrojournal.com ! 2014 Informa UK Ltd
Current Medical Research & Opinion
2014
Table 3. Miscellaneous autoimmune conditions associated with HCL. No. patients
Autoimmune condition
1 1 1 1 1
Multiple sclerosis Nephrotic syndrome UC AL amyloidosis AA amyloidosis
Characteristics
Reference
Good response to cladribine Immune mediated GN and cryoglobulinemia UC diagnosed in the setting of HCL treated with IFN-alpha Amyloidosis diagnosed after HCL Amyloidosis diagnosed after HCL
34 36 37 38 39
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
GN: glomerulonephritis; UC: ulcerative colitis; AL: amyloid light chain; AA: amyloid protein A.
reported case, MG preceded HCL33. HCL was also described in a patient with longstanding MS34. Both HCL and MS went on to respond to cladribine therapy (Table 3). As this is the only such case report in the literature, the relationship between HCL and MS remains to be further explored.
Other autoimmune conditions Membranoproliferative glomerulonephritis (MPGN) and membranous nephropathy were described in patients with CLL, non-Hodgkins lymphoma and HCL. MPGN in HCL is thought to be caused by the monoclonal immunoglobulin secreted by the B-cell clone35. Douglas et al.36 described a patient with nephrotic syndrome and HCL who was diagnosed with immune-mediated glomerulonephritis and cryoglobulinemia (Table 3). Pecorari37 reported a case of ulcerative colitis (UC) in a patient treated with interferon-alpha for HCL. The suggested mechanism for this occurrence was thought to be the imbalance between T-helper 1 and T-helper 2 cells as T-helper 2 cell excess is often seen in patients with UC. Both AL and AA amyloidosis were described in patients with HCL (Table 3)38,39. A clonal B-lymphocyte disorder, HCL is associated with systemic monoclonal immunoglobulin light chain production, which is also a requirement for the development of amyloid light-chain (AL) amyloidosis. It is not entirely clear however whether proliferating hairy cells are monoclonal with respect to Ig light chain type, while AL amyloidosis requires the presence of a monoclonal gammopathy38. AA proteins are characteristic deposits in secondary amyloidosis and are thought to be related to the chronic inflammatory state seen in HCL39. Interestingly, AA amyloidosis is not uncommonly seen with various collagen vascular disorders, known to be associated with HCL as well.
Discussion Since 1970s–80s, HCL has been associated with vasculitis, polyarthritis and thrombosis in an important number of patients. Given the fact that the above associations have ! 2014 Informa UK Ltd www.cmrojournal.com
lingered over half a century, we decided to analyze them further. HCL has been associated with different rheumatologic diseases such as PAN, LCV and GCA, which are known to have an autoimmune basis. Leading to blood vessel injury, these conditions tend to occur rather earlier than later in the course of HCL, and may be difficult to distinguish from HCL-related vasculitis. Arthritic syndromes similar to the ones in rheumatoid arthritis, systemic lupus or scleroderma have been described in patients with HCL. Joint involvement is usually symmetrical and most often mimics clinically rheumatoid arthritis; however, asymmetrical arthritis can also be seen in these patients. Used for the HCL therapy, cladribine was shown to arrest symptoms of both scleroderma and systemic lupus in several reports. PM and DM were also described in patients with HCL, and they presented at the diagnosis of HCL. Autoimmune blood disorders associated with HCL include various autoimmune cytopenias. AIHA is the most common cytopenia associated with HCL. The most prevalent type is the cold (anti-i) autoantibody AIHA that can be severe and even fatal. Other cytopenias associated with HCL include ITP, autoimmune neutropenia and PRCA. APS is an autoimmune thrombotic disorder associated with HCL, and usually presents at the diagnosis of HCL. APS seen in HCL can be primary or secondary to a collagen vascular disorder such as systemic lupus or rheumatoid arthritis. Antibody-mediated neuro-endocrine diseases are less common than autoimmune hematologic or rheumatologic conditions in patients with HCL. Rare reports of immune-mediated glomerulonephritis and cryoglobulinemia have also surfaced in patients with HCL. A large case–control study published by Anderson and Engels40 compared 418 cases of HCL with 160,086 controls and concluded that there was no overall increased prevalence of autoimmune conditions in patients with HCL. However, their study did in fact show increased prevalence of certain autoimmune conditions in HCL, namely ankylosing spondylitis (odds ratio [OR] 12.2, CI 1.7–90), erythema nodosum (OR 37, CI 4.9–284), Hashymoto thyroiditis (OR 10.3 CI 2.5–42.3), SLE (OR 7.2 CI 2.3–22.8), pernicious anemia (OR 3.4 CI 1.6–7.1), sarcoidosis (OR 9.6 CI 2.4–39.5) and Sjogren syndrome (OR 7.9 CI 1.1–57.5). Notably, these conditions were Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
5
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
2014
identified either prior to or at the moment of HCL diagnosis, but none thereafter. We also believe that some confounding variables in that study could have influenced the results. For instance, the control group included more female patients when compared to the HCL cohort (51% vs. 32%), which could have falsely increased the incidence of autoimmune disorders since women are at higher risk than men in that regard41. In addition, the study only included patients aged 67–99 but not younger which could have otherwise yielded different results. Furthermore, the control group included patients that were relatively younger than the HCL patients (46% vs. 37% patients were aged 67–74), and studies have shown the prevalence of autoimmune diseases to be higher in the 65–75 age group as opposed to subjects 75–85 years or older41. This could have shown a higher prevalence of autoimmune conditions in the control group compared with HCL group, leading to a type 2 error. Unfortunately, available literature on autoimmune conditions in HCL consists of mainly retrospective analyses of case series and isolated reports. This represents the weakness of our study as overgeneralizations may occur in this context. Retrospective design of the included case series may also limit the accuracy of our analysis. In addition, conclusions of the present study might render an overestimation of the association between autoimmune conditions and HCL. Furthermore, the possibility of publication bias is a valid concern for any synthetic and/or analytic reviews. It reflects the reality that studies reporting positive associations are more likely to be published than the ones reporting negative associations. Exclusion of studies published in other languages than English from the current systematic analysis might represent another potential source of publication bias. Finally, some associations between instances of autoimmunity and HCL could represent a mere coincidence as they may not be interrelated. Nonetheless, many of the published studies suggest potential common steps in the pathogenesis for both autoimmune conditions and HCL as these conditions more often than not present concurrently with HCL and tend to respond to the therapy with nucleoside analogs. Yet, the exact steps of pathogenesis underlying these disorders remain to be discovered. Close surveillance including regular follow-up could be important as early detection of autoimmune conditions may improve clinical outcomes in patients with HCL. Conversely, diagnosis of an autoimmune disease could lead to the HCL diagnosis as many autoimmune diseases present early in its course or may even precede HCL. However, due to lack of solid data, there are no specific guidelines in terms of optimal screening for autoimmunity in patients with HCL. Certainly, further studies including prospective data and cost–benefit analysis of intensive screening are warranted, and could help establish new guidelines for management of HCL patients. 6
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
Conclusions Patients with HCL present intricate immune alterations and an excess of autoimmune conditions. Autoimmune disorders can develop prior to, during or after the onset of HCL. Some of them could be secondary to the dysfunctional immune response associated with the underlying malignant process, while others might be primary and play a role in the HCL pathogenesis. In caring for patients with this rare chronic form of leukemia, many autoimmune complications are recognized. Knowing these manifestations is important not only for making a correct diagnosis at the patient’s initial presentation, but also for evaluating clinical events occurring during the course of the disease. There is a variety of clinical manifestations that do not always present in the identical manner, thus making recognition difficult. The rare nature and limited number of patients seen in any one center in a defined timeframe also complicate recognition and description of these disorders. The autoimmune complications can pose significant clinical problems for the HCL patients and their providers. Therefore, a catalog of these problems in HCL is important for alerting physicians to watch for them.
Transparency Declaration of funding This review was not funded. Declaration of financial/other relationships M.V.d.B., D.P., and J.A.-A. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. C.A.D. has disclosed that he is a member of CMRO’s Editorial Board but has no relevant financial or other relationships to disclose. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
References 1. Dasanu CA, Ichim TE, Alexandrescu DT. Inherent and iatrogenic immune defects in hairy cell leukemia: revisited. Expert Opin Drug Saf 2010;9:55-64 2. Polliack A. Hairy cell leukemia: biology, clinical diagnosis, unusual manifestations and associated disorders. Rev Clin Exp Hematol 2002;6:366-88 3. Tadmor T, Polliack A. Unusual clinical manifestations, rare sites of involvement, and the association of other disorders with hairy cell leukemia. Leuk Lymphoma 2011;52(Suppl 2):57-61 4. Kraut E. Clinical manifestations and infectious complications of hairy-cell leukemia. Best Pract Res Clin Haematol 2003;16:33-40 5. Robak T. Recent clinical trials of cladribine in hematologic malignancies and autoimmune disorders. Rev Recent Clin Trials 2006;1:15-34 6. Domingo A, Crespo N, Fernandez de Sevilla A, et al. Hairy cell leukemia and autoimmune hemolytic anemia. Leukemia 1992;6:606-7 7. Mainwaring CJ, Walewska R, Snowden J, et al. Fatal cold anti-I autoimmune hemolytic anaemia complicating hairy cell leukemia. Br J Haematol 2000;109:641-3
www.cmrojournal.com ! 2014 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by University of Waterloo on 12/12/14 For personal use only.
Current Medical Research & Opinion
8. Kipps TJ, Carson DA. Autoantibodies in chronic lymphocytic leukemia and related systemic autoimmune diseases. Blood 1993;81:2475-87 9. Virchis AE, Jan-Mohamed R, Kaczmarski KS, et al. Primary splenic hairy cell leukemia variant presenting as immune thrombocytopenic purpura. Eur J Haematol 1998;61:288-91 10. Diop S, Ndiaye MF, Farah F, et al. Hairy cell leukemia revealed by an isolated neutropenia. Dakar Med 2003;48:230-2 11. Quach H, Januszewicz H, Westerman D. Complete remission of hairy cell leukemia variant (HCL-v) complicated by red cell aplasia post treatment with rituximab. Haematologica 2005;90(Suppl):ECR26 12. Diz-kucukkaya R, Dincol G, Kamali S, et al. Development of hairy cell leukemia in a patient with antiphospholipid syndrome. Lupus 2007;16:286-8 13. Raju SF, Chapman SW, Dreiling B, et al. Hairy-cell leukemia with the appearance of mixed cryoglobulinemia and vasculitis. Arch Intern Med 1984;144:1300-2 14. Hasler P, Kistler H, Gerber H. Vasculitides in hairy cell leukemia. Semin Arthritis Rheum 1995;25:134-42 15. Hughes GR, Elkon KB, Spiller R, et al. Polyarteritis nodosa and hairy-cell leukaemia. Lancet 1979;1:678 16. Farcet JP, Weschsler J, Wirquin V, et al. Vasculitis in hairy cell leukemia. Arch Intern Med 1987;147:660-4 17. Fortin PR. Vasculitides associated with malignancy. Curr Opin Rheumatol 1996;8:30-3 18. Gabriel SE, Conn DL, Phyliky RL, et al. Vasculitis in hairy cell leukemia: review of literature and consideration of possible pathogenic mechanisms. J Rheumatol 1986;13:1167-72 19. Westbrook CA, Golde DW. Autoimmune disease in hairy-cell leukaemia: clinical syndromes and treatment. Br J Haematol 1985;61:349-56 20. Vernhes JP, Schaeverbeke T, Fach J, et al. Chronic immunity-driven polyarthritis in hairy cell leukemia. Report of a case and review of the literature. Rev Rhum Engl Ed 1997;64:578-81 21. Ehrlich J, Forer S. Periosteal ossification in Myelogenous leukemia. Arch Intern Med (Chic) 1934;53:938-52 22. Sattar MA, Cawley MI. Arthritis associated with hairy cell leukaemia. Ann Rheum Dis 1982;41:289-91 23. Zervas J, Vayopoulos G, Kaklamanis PH, et al. Hairy cell leukemia-associated polyarthritis. A report of two cases. Br J Rheumatol 1991;30:157-8 24. Blanche P, Bachmeyer C, Mikdame M, et al. Scleroderma, polymyositis and hairy cell leukemia. J Rheumatol 1995;22:1384-5 25. Naschitz JE, Rosner I, Rozenbaum M, et al. Rheumatic syndromes: clues to occult neoplasia. Semin Arthritis Rheum 1999;29:43-55
! 2014 Informa UK Ltd www.cmrojournal.com
2014
26. Juarez M, Marshall R, Denton C, et al. Paraneoplastic scleroderma secondary to hairy cell leukaemia successfully treated with cladribine. Rheumatology (Oxford) 2008;47:1734-5 27. Dasanu CA, Stoica-Mustafa E, Herlea V, et al. New therapies for patients with hairy cell leukemia at a glance: comprehensive review article with an illustrative case. Ann Fundeni Hosp 2005;10:75-8 28. Oo T, Delafuente M, Hassoun H. Possible association between hairy cell leukemia and Behc¸et’s disease. South Med J 2003;96:323-4 29. Marie I, Guillevin J, Menard JF, et al. Hematologic malignancy associated with polymyositis and dermatomyositis. Autoimmun Rev 2012;11:615-20 30. Zampieri S, Valente M, Adami N, et al. Polymyositis, dermatomyositis and malignancy: a further intriguing link. Autoimmun Rev 2010;9: 449-53 31. Strickland R, Limmani A, Wall JG, et al. Hairy cell leukemia presenting as lupus-like illness. Arthritis Rheum 1988;31:566-8 32. Harvey AM, Shulman LE, Tumulty PA, et al. Systemic lupus erythematosis: review of literature and clinical analysis of 138 cases. Medicine (Baltimore) 1954;33:291-437 33. Garcia-Giron C, Ferna´ndez de Castro M, Jime´nez Herra´ez C, et al. The association of myasthenia gravis and hairy cell leukemia. Med Clin (Barc) 1991;97:703-5 34. Hilbe W, Berger T, Konwalinka G, et al. Cladribine treatment of a patient with hairy cell leukemia and concomitant multiple sclerosis. Acta Haematol 1999;102:99-100 35. Favre G, Courtellemont C, Callard P, et al. Membranoproliferative glomerulonephritis, chronic lymphocytic leukemia, and cryoglobulinemia. Am J Kidney Dis 2010;55:391-4 36. Douglas MF, Schwartz MM, Sharon Z. Cryoglobulinemia and immunemediated glomerulonephritis in association with hairy cell leukemia. Am J Kidney Dis 1985;6:181-4 37. Pecorari P. Ulcerative colitis in hairy cell leukemia. A case report. Recenti Prog Med 1991;82:269-71 38. Benson MD, Kramer G, Abonour R. Hairy cell leukemia and light chain (AL) amyloidosis: a case report. Amyloid 2011;18(Suppl 1):101-2 39. Linder J, Silberman HR, Croker BP. Amyloidosis complicating hairy cell leukemia. Am J Clin Pathol 1982;78:864-7 40. Anderson LA, Engels EA. Autoimmune conditions and hairy cell leukemia: an exploratory case–control study. J Hematol Oncol 2010;3:35 41. Crowson CS, Matteson EL, Myasoedova E, et al. The lifetime risk of adultonset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum 2011;63:633-9
Autoimmune disorders in patients with hairy cell leukemia Dasanu et al.
7
