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Systemic antineutrophil cytoplasmic antibody vasculitis in a patient with chronic lymphocytic leukemia - Quite a rare diagnosis
Abstract
There might be rheumatic manifestations of malignant diseases, especially those of the hematological type. Until now, antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in chronic lymphocytic leukemia (CLL) has been reported on only very few occasions. Here, we present our patient with Rai stage II CLL who came to us with constitutional symptoms. She turned out to have hematuria with dysmorphic erythrocytes and developed hemoptysis. She had pulmonary-renal syndrome and was diagnosed with p-ANCA positive microscopic polyangiitis. She is currently using prednisolone and cyclophosphamide and undergoing regular hemodialysis. Constitutional symptoms in patients with hematological malignancies should make the physicians consider systemic vasculitis after exclusion of disease-related complications.
... The dermatological lesions presented at that moment were interpreted as post-drug-fixed erythematic lesions, being treated with prednisolone 32 mg/day, with the decreasing of the doses and treatment cessation after 6 weeks. The repeated respiratory infections were considered to result from the chronic lymphocytic leukemia, caused by the severe immune deficit, and the case was not investigated for vasculitis, this situation being rarely described in the literature [2,3]. The association of eyehole cellulites with the rhino sinusal lesions on the same region (Fig. 2) completed the clinical aspect with elements which are related to Wegener's granulomatosis, confirmed by biopsy and by positive c-ANCAs, a situation which is rarely described in the literature [4,5] in association with chronic lymphocytic leukemia. ...
... The eye lesions were also associated with all of these, which are described in more than half of the cases with Wegener's granulomatosis [8]: the inflammatory eyehole disease, scleritis, chemosis, maxillary sinus lesions, and left frontal and ethmoidal lesions, confirmed by biopsy. The severe neutropenia which the patient presented was probably due to the presence of ANCA [3], while the low platelet number was a consequence of the chronic lymphocytic leukemia [9]. Because of the immune deficit (during the evolution of chronic lymphocytic leukemia), hypogammaglobulinemia, complement deficit [10][11][12], and corticotherapy, the patient presented a high risk of respiratory tract infections with encapsulated bacteria-K. ...
Background
Wegener’s granulomatosis is a systemic vasculitis of the small- and medium-sized vessels, produced by the action of ANCA, which involves the respiratory tract, kidneys, and eyes, with a potential for lethal evolution in the first year after diagnosis. Its association with chronic lymphocytic leukemia is rarely described in the literature, and it may be difficult to diagnose and to treat this association.
Case presentation
We present the case of a 73-year-old Caucasian patient, a rare case in which Wegener’s granulomatosis is associated in a patient with chronic lymphocytic leukemia, who is admitted in the Infectious Disease Department for fever, diplopia, headache, purulent and hemorrhagic nasal secretions, intense asthenia, and weight loss. The patient had associated eyelid edema; scleritis; chemosis; subconjunctival hemorrhage at the left eye; swelling of the left region of the eyehole, of the base of the nasal pyramid, and of the left zygomatic region; anterior nasal bleeding; pustulous non-itching lesions at the cervical region and posterior thorax; enlarged bilateral axillary lymph nodes; hepatomegaly; and moderate splenomegaly. During the surgical treatment of the pansinusitis, a biopsy from the tissue is taken; the biopsy fragments of the nasal mucosa pleads for Wegener’s granulomatosis. The c-ANCA were positive. The patient’s evolution was favorable under treatment with meropenem, teicoplanin, fluconazole, transfusions of platelet concentrates, and methylprednisolone.
Conclusions
The real dimension of the association between chronic lymphocytic leukemia and Wegener’s granulomatosis is not known; it may be useful to evaluate the vasculitis by testing ANCA routinely in patients with chronic lymphocytic leukemia and by histopathological examinations of the lesions.
... It should be also remembered that, besides cutaneous vasculitis, HMs can induce a broad spectrum of systemic vasculitis, which can present with a secondary involvement of the skin, including giant-cell arteritis, large-and medium-vessel vasculitis, anti-neutrophil cytoplasmic antibody-associated vasculitis and Behçet's disease [192,[197][198][199][200][201][202]. ...
Haematological malignancies induce important alterations of the immune system, which account for the high frequency of autoimmune complications observed in patients. Cutaneous immune-mediated diseases associated with haematological malignancies encompass a heterogeneous group of dermatoses, including, among others, neutrophilic and eosinophilic dermatoses, autoantibody-mediated skin diseases, vasculitis and granulomatous dermatoses. Some of these diseases, such as paraneoplastic pemphigus, are associated with an increased risk of death; others, such as eosinophilic dermatoses of haematological malignancies, run a benign clinical course but portend a significant negative impairment on a patient’s quality of life. In rare cases, the skin eruption reflects immunological alterations associated with an unfavourable prognosis of the associated haematological disorder. Therapeutic management of immune-mediated skin diseases in patients with haematological malignancies is often challenging. Systemic corticosteroids and immunosuppressive drugs are considered frontline therapies but may considerably augment the risk of serious infections. Indeed, developing a specific targeted therapeutic approach is of crucial importance for this particularly fragile patient population. This review provides an up-to-date overview on the immune-mediated skin diseases most frequently encountered by patients with onco-haematological disorders, discussing new pathogenic advances and therapeutic options on the horizon.
... Neuro-GSS is only one example of possible autoimmune disease with neurological involvement that can be found associated with CLL. A literature review highlighted other potentially tricky situations: associated rheumatoid [10], ANCA-associated [11] or leukocytoclastic vasculitis that can lead to specific lesions of the central or peripheral nervous systems; lupus erythematosus [12] with CNS involvement; dysthyroidal encephalopathy [13]; manifestations related to monoclonal gammopathy that remain only peripheral (anti-MAG associated polyneuropathy and induced Guillain-Barré syndrome). ...
... Most of these CLL-associated cases are single patient case reports or small case series, with the largest report to date including 15 patients. [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] Here we report the pathological findings and outcomes of a series of 49 patients with CLL and MBL followed at a single institution, who underwent a kidney biopsy during the course of their disease to evaluate renal insufficiency and/or nephrotic syndrome. ...
While the renal complications of plasma cell dyscrasia are well-described, most information in patients with chronic lymphocytic leukemia and monoclonal B lymphocytosis is derived from case reports. This is a retrospective analysis of patients with chronic lymphocytic leukemia or monoclonal B lymphocytosis who underwent a kidney biopsy for renal insufficiency and/or nephrotic syndrome. Between 01/1995 and 06/2014, 49 of 4024 (1.2%) patients with chronic lymphocytic leukemia (44) or monoclonal B lymphocytosis (5) had a renal biopsy: 34 (69%) for renal insufficiency and 15 (31%) for nephrotic syndrome. The most common findings on biopsy were: membranoproliferative glomerulonephritis (n=10, 20%), chronic lymphocytic leukemia interstitial infiltration as primary etiology (n=6, 12%), thrombotic microangiopathy (n=6, 12%), and minimal change disease (n=5, 10%). All 5 membranoproliferative glomerulonephritis patients treated with rituximab, cyclophosphamide and prednisone based regimens had recovery of renal function compared to 0/3 patients treated with rituximab +/- steroids. Chronic lymphocytic leukemia infiltration as the primary cause of renal abnormalities was typically observed in relapsed/refractory patients (4/ 6). Thrombotic microangiopathy primarily occurred as a treatment related toxicity due to pentostatin (4/6 cases), and resolved with drug discontinuation. All cases of minimal change disease resolved with immunosuppressive agents only. Renal biopsy plays an important role in the management of patients with chronic lymphocytic leukemia or monoclonal B lymphocytosis who develop renal failure and/or nephrotic syndrome.
Copyright © 2015, Ferrata Storti Foundation.
... 7 Raros casos manifestam granulocitopenia autoimune, e acredita-se que ela esteja relacionada à presença de ANCA. 8 Depois de um tempo assintomático, o doente evoluiu com manifestações pulmonares. O aspecto tomográfico era inespecífico, mas compatível com manifestações da GW, e a biopsia pulmonar afastava LLC. ...
The aim of the present work is to discuss the report of a patient who had simultaneous diagnosis of two rare diseases, vasculitis related to antineutrophil cytoplasmic antibodies and chronic lymphocytic leukemia. Both are diseases that may be multisystemic and thus cause diagnostic confusion. In this case, the patient had renal, pulmonary, hematological, and ocular symptoms, which could be secondary to vasculitis both as to leukemia. With the aid of imaging studies, pathological studies, immunohistochemistry and immunopheno- typing, we conclude that it was a combination of the two diseases. There are other reports in literature of this association, however, with pANCA positive, this is the first report of chronic lymphocytic leukemia associated with cANCA positive vasculitis.
... 7 Rare cases manifest autoimmune granulocytopenia, and it is believed that this complication is related to the presence of ANCA. 8 After an asymptomatic period, the patient developed lung manifestations. The CT appearance was nonspecific, but consistent with manifestations of WG, and a lung biopsy discarded the possibility of CLL. ...
The aim of the present work is to discuss the report of a patient who had simultaneous diagnosis of two rare diseases, vasculitis related to antineutrophil cytoplasmic antibodies and chronic lymphocytic leukemia. Both are diseases that may be multisystemic and thus cause diagnostic confusion. In this case, the patient had renal, pulmonary, hematological, and ocular symptoms, which could be secondary to vasculitis both as to leukemia. With the aid of imaging studies, pathological studies, immunohistochemistry and immunophenotyping, we conclude that it was a combination of the two diseases. There are other reports in literature of this association, however, with pANCA positive, this is the first report of chronic lymphocytic leukemia associated with cANCA positive vasculitis.
Context.—Nonneoplastic kidney diseases, such as arterionephrosclerosis and/or diabetic nephropathy, are commonly encountered in tumor nephrectomy and nephroureterectomy specimens. Although any nonneoplastic kidney disease may be encountered in these resection specimens by chance, additional diseases that may be related to the underlying neoplasm or its treatment regimen include thrombotic microangiopathy, Amyloid A amyloidosis, membranous nephropathy, immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, pauci-immune crescentic glomerulonephritis, focal segmental glomerulosclerosis, minimal-change disease, acute interstitial nephritis, and xanthogranulomatous pyelonephritis. Given the morbidity of chronic kidney disease and the relatively favorable 5-year survival rates for urothelial and renal cell carcinomas, accurate evaluation of the nonneoplastic kidney parenchyma is important.
Objectives.—We will discuss our approach for evaluating the nonneoplastic kidney parenchyma in tumor nephrectomy and nephroureterectomy specimens. The pathologic features of the aforementioned kidney diseases as well as pertinent references will be reviewed. The identification of glomerular abnormalities, including mesangial sclerosis or hypercellularity, segmental sclerosis, crescent formation, glomerulitis, or glomerular basement membrane alterations, should lead to additional immunofluorescence and electron microscopic studies. Safeguards to ensure that the nonneoplastic parenchyma is not overlooked include adding this important parameter to synoptic reports and obtaining periodic acid–Schiff and/or Jones methenamine silver stains prior to microscopic evaluation of the neoplasm.
Data Sources.—Relevant literature and University of Chicago Medical Center pathology archives.
Conclusions.—The practicing surgical pathologist should be aware of the importance of both correctly classifying the resected renal or urothelial neoplasm and the concomitant nonneoplastic kidney disease that may be present in these specimens.
We report a novel case of a patient who presented with new diagnoses of both cytoplasmic antineutrophil cytoplasmic antibodies (c-ANCAs) positive vasculitis and chronic lymphocytic leukaemia (CLL). The patient was a 79-year-old man who presented with melena, haemoptysis, acute hypoxia and acute kidney injury. In the current literature, there are rare associations of c-ANCA vasculitis and malignancy, but very few, if any, relating c-ANCA vasculitis and CLL. This case is unique due to the presence of both pathologies and an uncommon presentation of the vasculitis. He presented with renal and pulmonary findings, unlike the dermal manifestations commonly seen with vasculitis. We think that this could be an easily overlooked combination of diseases and, therefore, the purpose of this case is to prevent delays in care that could affect patient outcomes and also to encourage further research into the relationship between these diseases.
Background:
The most common paraneoplastic vasculitis is leukocytoclastic vasculitis (LCV),(1) 75% of which are caused by hematological malignancies. Chronic lymphocytic leukemia (CLL) is associated with a multitude of auto-immune paraneoplastic syndromes. Data on LCV in association with CLL is restricted to isolated case reports,(3,4) none of which had systemic LCV. We present a unique case of fatal paraneoplastic, systemic LCV as an initial presentation of CLL in an elderly male with multiple co-morbidities.
Case:
A 71-year-old man presented with a palpable, symmetric, purpuric rash on the lower extremities and an absolute lymphocytosis (white blood cell count 26.9; 23% lymphocytes). His co-morbidities included coronary artery disease, congestive heart failure, and new critical aortic stenosis. Flow cytometry of peripheral blood demonstrated an abnormal population of B-cells, positive for CD5, CD19, and CD23, consistent with CLL. The skin biopsy specimen revealed neutrophilic inflammation in vessel walls indicative of LCV. Acute renal failure (creatinine 2 mg/dL), urinary red cell casts, and hypocomplementemia were concerning for a systemic vasculitis. The antinuclear antibody, cryoglobulin titer, antineutrophil cytoplasmic antibody, serum protein electrophoresis, viral serologies were negative. On hospital day 6, he developed acute hepatocellular injury and acute respiratory failure. Continuous veno-venous hemodialysis was begun for worsening acidemia and hyperkalemia. Two days later he became obtunded on hospital day 8 and had an elevated lactic acid level with generalized abdominal tenderness worrisome for bowel ischemia. The same day he needed intubation with cardiopulmonary resuscitation for a brief episode of asystole. Despite aggressive treatment with high-dose steroids and plasmapheresis, he suffered worsening renal failure and shock. His family sought withdrawal of care on hospital day 11. Autopsy revealed diffuse LCV of the stomach, distal ileum, integument and alveoli with petechial hemorrhages, fibrin thrombi, and gangrenous patchy necrosis.
Conclusion:
Paraneoplastic LCV is a rare syndrome and seldom occurs in association with CLL. This is the first reported case of fatal systemic paraneoplastic LCV from B-cell CLL. Dermatologic involvement is universal with LCV, and may portend systemic disease. More data on its pathogenesis in CLL is warranted.
Chronic lymphocytic leukemia is frequently associated with immune disturbances. The relationship between chronic lymphocytic leukemia and autoimmune cytopenias, particularly autoimmune hemolytic anemia and immune thrombocytopenia, is well established. The responsible mechanisms, particularly the role of leukemic cells in orchestrating the production of polyclonal autoantibodies, are increasingly well understood. Recent studies show that autoimmune cytopenia is not necessarily associated with poor prognosis. On the contrary, patients with anemia or thrombocytopenia due to immune mechanisms have a better outcome than those in whom these features are due to bone marrow infiltration by the disease. Moreover, fears about the risk of autoimmune hemolysis following single agent fludarabine may no longer be appropriate in the age of chemo-immunotherapy regimens. However, treatment of patients with active hemolysis may pose important problems needing an individualized and clinically sound approach. The concept that autoimmune cytopenia may precede the leukemia should be revisited in the light of recent data showing that autoimmune cytopenia may be observed in monoclonal B-cell lymphocytosis, a condition that can only be detected by using sensitive flow cytometry techniques. On the other hand, there is no evidence of an increased risk of non-hemic autoimmune disorders in chronic lymphocytic leukemia. Likewise, there is no epidemiological proof of an increased risk of chronic lymphocytic leukemia in patients with non-hemic autoimmunity. Finally, since immune disorders are an important part of chronic lymphocytic leukemia, studies aimed at revealing the mechanisms linking the neoplastic and the immune components of the disease should help our understanding of this form of leukemia.
We report a 69-year-old African American woman with hemoptysis and hematuria caused by a focally crescentic pauci-immune glomerular injury associated with the presence of antineutrophil cytoplasmic antibodies (ANCAs). An incidental diagnosis of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma also was established based on the kidney biopsy. Given that a subset of patients with CLL can develop autoantibodies to red blood cells, platelets, or, rarely, neutrophils, the simultaneous presence of CLL, ANCA, and a pauci-immune crescentic glomerulonephritis may not be a coincidence. Recent advances in the pathogenic role of ANCAs in pauci-immune crescentic glomerulonephritis may link the underlying CLL to this patient's glomerular injury. Awareness of this possible association may be important for clinicians who manage patients with CLL, as well as for renal pathologists who diagnose pauci-immune crescentic glomerulonephritis.
Microscopic polyangiitis (MPA) is a member of the family of ANCA-associated vasculitides. Its characteristic histology shows a necrotizing small vessel vasculitis with little or absent immune deposits (pauci-immune vasculitis). In Western countries MPA shows a lower prevalence than Wegener's disease, it affects more men than women and commences at the age of > or = 50 years. The two organs most typically involved and often defining prognosis are the kidneys and the lungs. MPA may concomitantly or sequentially involve other organs such as the nervous system, the skin, the musculoskeletal system, but also the heart, the eye and the intestines. Treatment decisions should be based on severity and pattern of organ involvement and respect the five factor score (FFS). Life- or organ- threatening disease is treated with glucocorticoids and (pulse) cyclophosphamide. Plasmapheresis and i.v.immunoglobulins have been shown to be beneficial as additional measure in severe cases. If renal function is preserved, Methotrexate may be considered to induce remission, and if the FFS equals 0, remission may be induced with glucocorticoid monotherapy. Maintenance therapy is recommended with Azathioprin, mycophenolate mofetil may be used as a second line drug. Biologic agents such as monoclonal antibodies to tumor necrosis factor a and B cell depleting rituximab have been shown to bear remission-inducing quality.
Nonneoplastic kidney diseases, such as arterionephrosclerosis and/or diabetic nephropathy, are commonly encountered in tumor nephrectomy and nephroureterectomy specimens. Although any nonneoplastic kidney disease may be encountered in these resection specimens by chance, additional diseases that may be related to the underlying neoplasm or its treatment regimen include thrombotic microangiopathy, Amyloid A amyloidosis, membranous nephropathy, immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, pauci-immune crescentic glomerulonephritis, focal segmental glomerulosclerosis, minimal-change disease, acute interstitial nephritis, and xanthogranulomatous pyelonephritis. Given the morbidity of chronic kidney disease and the relatively favorable 5-year survival rates for urothelial and renal cell carcinomas, accurate evaluation of the nonneoplastic kidney parenchyma is important.
We will discuss our approach for evaluating the nonneoplastic kidney parenchyma in tumor nephrectomy and nephroureterectomy specimens. The pathologic features of the aforementioned kidney diseases as well as pertinent references will be reviewed. The identification of glomerular abnormalities, including mesangial sclerosis or hypercellularity, segmental sclerosis, crescent formation, glomerulitis, or glomerular basement membrane alterations, should lead to additional immunofluorescence and electron microscopic studies. Safeguards to ensure that the nonneoplastic parenchyma is not overlooked include adding this important parameter to synoptic reports and obtaining periodic acid-Schiff and/or Jones methenamine silver stains prior to microscopic evaluation of the neoplasm.
Relevant literature and University of Chicago Medical Center pathology archives.
The practicing surgical pathologist should be aware of the importance of both correctly classifying the resected renal or urothelial neoplasm and the concomitant nonneoplastic kidney disease that may be present in these specimens.
Immunoglobulin G (IgG) autoantibodies against extranuclear components of polymorphonuclear granulocytes were detected in 25 of 27 serum samples from patients with active Wegener's granulomatosis and in only 4 of 32 samples from patients without signs of disease activity. In a prospective study of 19 patients these antibodies proved to be better markers of disease activity than several other laboratory measurements used previously. The autoantibodies were disease specific and the titres were related to the results of an in-vitro granulocyte phagocytosis test, in which 7S IgG antibodies were internalised after specific binding to the cell, resulting in gradual formation of ring-like cytoplasmic structures. This autoantibody may have a pathogenetic role in Wegener's granulomatosis. The detection of this antibody is valuable for diagnosis and estimation of disease activity.
Fifty-two cases of autoimmune hemolytic anemia (AHA) were observed within a series of 1203 patients (4.3%) with chronic lymphocytic leukemia (CLL) followed at a single institution. Nineteen were observed at the time of CLL diagnosis and 33 during the clinical follow-up. Ninety percent of the patients with CLL/AHA showed active CLL and 25% had been treated previously. The antierythrocyte autoantibody (AeAb) was an IgG in 87% of cases and an IgM in 13%. A lymphocyte count more than 60 x 10(9)/L (P <.00001), age above 65 years (P <.01), and male gender (P <.01) emerged as independent parameters that correlated significantly with an increased rate of AHA at CLL diagnosis. Patients previously treated with chlorambucil (CB) plus prednisone (PDN) and with fludarabine plus PDN showed a similar rate of AHA (1.8% and 2.5%, respectively). After steroid therapy associated with CB in case of active CLL, 70% of patients achieved the complete disappearance of the AeAb. The actuarial AHA relapse-free survival probability was 54% at 5 years and the median survival probability after AHA was 41 months. Infections represented the main cause of morbidity and mortality. IgG AHA and the occurrence of AHA at the same time of CLL diagnosis emerged as independent factors significantly correlated with a better survival probability of AHA/CLL patients. Taken together, this study indicates that in CLL, AHA is a rare event with no independent effect on survival for which steroids, associated with CB if required, and a careful management of infections may successfully control the 2 conditions. Cooperative studies are needed to better define the optimal steroid schedule and the therapeutic role of other immunosuppressive agents and splenectomy. (Blood. 2000;95:2786-2792)
BACKGROUND
The natural history of chronic lymphocytic leukemia (CLL) is changing, although the reasons (potential changes in the disease's biology or in patterns in patient characteristics, treatment, or referral) are unclear.METHODS
This report uses National Cancer Data Base (NCDB) data, which reflect a hospital-based patient population from a broad spectrum of hospitals in the United States. Age, gender, race/ethnicity, income, treatment, overall survival, and relative survival were evaluated according to time period (1985–1990 and 1991–1995). Comparisons were made with U.S. population figures for 1990 and with series published over the last 70 years.RESULTSCLL comprised 22.6% of the 108,396 cases of leukemia in the data base. The risk of developing CLL increased progressively with age and did not plateau; the average age was 69.6 years. At the time of initial diagnosis, 60.5% of patients received no treatment (this proportion increased from 58.1% to 62.7% between the 2 time periods). Overall survival was 48.2% at 5 years and 22.5% at 10 years. The 5-year relative survival was 69.5%, 72.2%, 63.1%, and 41.7% for age groups <40, 40–59, 60–79, and 80+ years, respectively; these rates indicated that CLL, and not comorbid disease, caused the greatest percentage of deaths.CONCLUSIONS
The risk of developing CLL increases progressively with age without plateauing and is 2.8 times higher for older men than for older women. There is an increasing trend toward no treatment at the time of initial diagnosis. Long term overall survival of CLL patients is poor. CLL is a more fatal disease among older individuals because of the disease itself, not because of comorbid conditions. Cancer 1999;86:2684–92. © 1999 American Cancer Society.
A large variety of vasculopathic syndromes are uncommonly associated with malignancies. Vasculitis is usually manifested by skin lesions and is generally associated with hematologic malignancies rather than solid tumors. Evidence of autoantibodies, immune complexes, and complement consumption is typically absent. Myelodysplastic syndromes can be confidently linked to vasculitis on the basis of recent literature. The temporal relationship of malignancy to vasculitis development is variable except that vasculitis generally follows the discovery of hairy cell leukemia and splenectomy. Vasculitis may occasionally be a complication of chemotherapy, radiation therapy, and bone marrow transplantation. Occasionally, malignant disorders may mimic vasculitic syndromes. The etiopathogenesis of vasculitis in patients with malignant disorders is unknown. The recent literature on vasculitis and malignancy addresses predominantly case reports and small patient cohorts and identifies clinical characteristics rather than pathogenic mechanisms.
The current literature on human CD5-positive B cells (CD5 + B cells) has been analysed, with a special emphasis on non organ-specific auto-immune diseases. Malignant cells of most of the chronic lymphoid leukaemias of the B cell lineage express the CD5 molecule. Antibodies of the IgM class produced by leukaemic B cells are multispecific auto-antibodies. The CD5 + B cell subset may be expanded in non organ-specific autoimmune diseases, such as rheumatoid arthritis, primary Sjögren's syndrome, systemic lupus erythematosus. This holds true for various conditions, including organ-specific auto-immune diseases. Since auto-immune features are common in lymphoproliferative disorders, and the latter be a complication in non organ-specific auto-immune diseases, CD5 + B cells may represent an intermediary between these auto-immune diseases and B cell lymphoproliferations. Studies on the regulation of CD5 + B cell production and function are likely to shed light on the aetiology of, and pathogenetic mechanisms operating in the different disease states.
Interest in the rheumatologic manifestations of cancer is related in part to practical considerations, ie, earlier cancer diagnosis is possible through enhanced awareness of cancer-associated rheumatic syndromes. The spectrum of rheumatic disorders associated with cancer includes over 30 conditions, including hypertrophic osteoarthropathy, polymyalgia rheumatica, palmar fasciitis with polyarthritis, most autoimmune connective tissue diseases, and the more recently described antiphospholipid syndrome. It is generally held that extensive search for occult malignancy in most rheumatologic disorders is not cost efficient and not recommended unless accompanied by specific findings suggestive of malignancy. The present article discusses the supplementary findings that may justify malignancy evaluation.
In a study of 94 patients with myelodysplastic syndrome (MDS) associated vasculitis was observed in 5, which preceded hematologic diagnosis in 4. Leukocytoclastic vasculitis was observed in 5 cases being associated to lobular panniculitis in one. Three patients had refractory anemia, one sideroblastic anemia (SA) and another refractory anemia with excess blasts (RAEB). In the latter case lymphomatoid papulosis was also observed which, to date, has not been previously described in association with MDS. Another case presented seronegative polyarthritis and renal disease coinciding with vasculitis. Polyarteritis nodosa was diagnosed in a third patient in agreement with the criteria of the American College of Rheumatology, the association of which with MDS is exceptional. In the same case medullary cytogenetic study showed 46, XY,t (12;20), an abnormally which has not been described to date in cases of MDS. All the cases were treated with glucocorticoids in addition to cyclophosphamide in the patient with polyarteritis nodosa, with an improvement in the vasculitis being observed in all the patients. Two patients died, one (SA) due to pneumonia and the other (RAEB) due to subdural hematoma following transformation to acute myeloblastic leukemia. With 5% of the MDS studied presenting vasculitis, this syndrome should be included in the differential diagnosis of vasculitis observed in patients with cytopenia.
Forty-two cases of vasculitis coincident with hairy cell leukemia (HCL) have been reported, of which 17 had panarteritis nodosa (PAN), 21 had cutaneous leukocytoclastic vasculitis (LCV), and 4 had vessel wall infiltration by hairy cells. PAN generally occurred after the diagnosis of HCL, splenectomy, and infection. HBs antigen was detected in 3 of 12 patients tested, whereas immune complexes were positive in 3 of 4 patients tested. LCV was often preceded by infection and was frequently detected before HCL. Serum immunoglobulin levels were generally elevated when measured. Cryoglobulins, complement, rheumatoid factor, and antinuclear antibodies showed no clear association with vasculitis in HCL. These reports suggest a role for infection and splenectomy as contributing factors to vasculitis.
Vasculitis as a complication of lymphoproliferative diseases is relatively uncommon. Cutaneous vasculitis is most commonly necrotizing and leukocytoclastic. Granulomatous vasculitis occurs rarely with lymphoproliferative diseases, and even less commonly T-cell lymphocytic vasculitis with eosinophilia. The most common systemic vasculitis is caused by cryoglobulinemia, due to either lymphocytic lymphoma or Waldenström's macroglobulinemia. Other unusual associations involving systemic vasculitides include polyarteritis nodosa and hairy cell leukemia, Wegener's granulomatosis and Hodgkin's disease, granulomatous angiitis of the central nervous system and lymphoma, temporal arteritis and lymphoma, and Henoch-Schönlein purpura and lymphoma. The vasculitis may predate the diagnosis of the lymphoproliferative disease, and patients with vasculitis should be screened and monitored for lymphoproliferative diseases.
The prevalence of some autoantibodies in the elderly population has been reported to be greater than in younger controls. The prevalence of ANCA has been shown to be low in a generally healthy population, but has not been established in the elderly. Thus, the presence of ANCA in elderly patients might not have the same clinical significance as in younger people. The aim of this study was to evaluate the prevalence of ANCA in elderly subjects.
Serum samples from 137 subjects (96 females, 41 males; mean age = 82.2 years +/- 6.97 SD) were evaluated. Criteria for exclusion included suspected or established systemic vasculitis, connective tissue or neoplastic diseases, acute infection, HIV infection, current therapy with corticosteroids or cytotoxic drugs, and recent blood transfusion. ANCA were detected by indirect immunofluorescence on ethanol-fixed normal human neutrophils. Fluorescence patterns were classified as c-ANCA, p-ANCA or nuclear. Sera exhibiting p-ANCA or nuclear fluorescence were further tested by IIF on formalin-acetone fixed normal human neutrophils. Sera whose reaction pattern was cytoplasmic were considered as positive for "true" pANCA. Additionally, sera were tested for the presence of antinuclear antibodies (IIF), anti-double-stranded DNA (enzyme immunoassay) and IgM rheumatoid factors (enzyme immunoassay).
The prevalence of c-ANCA was 0% (95% CI = 0-2.66), the prevalence of p-ANCA was 2.2% (95% CI = 0.45-6.3), and the prevalence of "true" p-ANCA was 0.73% (95% CI = 0.02-4). The prevalence of ANA, anti ds-DNA and RF were respectively 38%, 3.6%, and 11.7%.
The prevalence of ANCA is not increased in elderly people. Thus, the presence of ANCA in elderly subjects may have the same clinical significance as in younger people.
Coexistence of a systemic vasculitis and an epithelioma is rare. The prevalence of malignancies in patients with vasculitis has been estimated at about 5%, with about two thirds hematological malignancies and one third solid tumors, although the actual figure may be higher. We report three cases of vasculitis in patients with solid tumors. A review of the literature yielded 77 additional cases. A total of 56 cases were fully documented. The sex ratio was 1.26, and mean age was 62.5 years. The most common vasculitides were leukocytoclastic vasculitis (33%), polyarteritis nodosa (16.5%) and Henoch-Schönlein purpura. The most common sites of cancer formation were the lung (23%), the digestive system (17.5%) and the kidney (14%). The diagnosis of vasculitis antedated that of cancer in most patients. Radical cancer treatment was often followed by resolution of the vasculitis and vasculitis recurrences occurred concomitantly with tumor recurrences in some patients, suggesting that the vasculitis was a paraneoplastic syndrome. Patients with unexplained chronic vasculitis with or without a history of cancer should undergo extensive investigations for an occult neoplasm.
Immune dysregulation, a hallmark of chronic lymphocytic leukemia (CLL), manifests itself in three autoimmune diseases: warm autoimmune hemolytic anemia (AIHA); idiopathic thrombocytopenia (ITP); and, pure red cell aplasia (PRCA). AIHA occurs in 11% of advanced stage CLL patients. Prednisone is the first treatment of choice, with 90% responses and 65% complete responses. More than 60% of patients relapse when treatment is stopped. Intravenous immunoglobulin, the next line of treatment, causes responses in 40% of patients. While the data are very limited, cyclosporine A is a reasonable choice for third-line therapy. Alkylating agents, danazol, plasma exchange, immunoabsorption, vincristine-loaded platelets, splenectomy, and splenic irradiation are also reported to cause responses. The data on mechanisms of AIHA are most consistent with immune dysregulation leading to loss of tolerance to a self antigen which in turn leads to the immune-based hemolytic anemia. PRCA is underrecognized in CLL with 6% of CLL patients having PRCA when tested for it. Unlike AIHA, PRCA often occurs in early stage disease. Anemia, reticulocytopenia, and a marrow virtually devoid of red blood cell precursors are hallmarks of PRCA. Corticosteroid therapy is the first line of treatment. If a response is not obtained in 4 weeks, cyclosporine A should be added. Although the data on pathophysiology are very limited, PRCA appears to be the result of an abnormal T cell that both fails in its normal function to support growth and inhibits the growth of erythroid progenitor cells. ITP occurs in 2-3% of CLL patients, occurs in early stage disease and may be a presenting manifestation. Initial therapy for ITP mirrors the guidelines for primary ITP. Initial therapy should consist of prednisone. Seventy percent of patients respond. Splenectomy is a reasonable second-line treatment. Autoimmune phenomena, largely related to blood cells, are based in the immune dysregulation of CLL. Longer survivals in CLL patients, more treatment regimens per patient, and more immunosuppression with modern treatments, allow us to predict an increasing incidence of autoimmune blood cell diseases in CLL.
The natural history of chronic lymphocytic leukemia (CLL) is changing, although the reasons (potential changes in the disease's biology or in patterns in patient characteristics, treatment, or referral) are unclear.
This report uses National Cancer Data Base (NCDB) data, which reflect a hospital-based patient population from a broad spectrum of hospitals in the United States. Age, gender, race/ethnicity, income, treatment, overall survival, and relative survival were evaluated according to time period (1985-1990 and 1991-1995). Comparisons were made with U. S. population figures for 1990 and with series published over the last 70 years.
CLL comprised 22.6% of the 108,396 cases of leukemia in the data base. The risk of developing CLL increased progressively with age and did not plateau; the average age was 69.6 years. At the time of initial diagnosis, 60.5% of patients received no treatment (this proportion increased from 58.1% to 62.7% between the 2 time periods). Overall survival was 48.2% at 5 years and 22.5% at 10 years. The 5-year relative survival was 69.5%, 72.2%, 63.1%, and 41.7% for age groups <40, 40-59, 60-79, and 80+ years, respectively; these rates indicated that CLL, and not comorbid disease, caused the greatest percentage of deaths.
The risk of developing CLL increases progressively with age without plateauing and is 2.8 times higher for older men than for older women. There is an increasing trend toward no treatment at the time of initial diagnosis. Long term overall survival of CLL patients is poor. CLL is a more fatal disease among older individuals because of the disease itself, not because of comorbid conditions.
To evaluate the prevalence of antineutrophil cytoplasmic antibodies (ANCA) and rheumatic manifestations associated with chronic haematological malignancies.
Two groups of patients were prospectively studied (group I: 60 patients with myelodysplastic syndromes and group II: 140 patients with lymphoid malignancies) for clinical 'immune' manifestations and ANCA.
In the myelodysplastic group, six patients had ANCA-negative systemic medium-size vasculitis, one had systemic vasculitis with cytoplasmic ANCA, one relapsing polychondritis, one giant cell arteritis, one polymyalgia rheumatica, one polyarthritis and two fasciitis. In group II, two patients had ANCA-negative systemic vasculitis, two had leucocytoclastic vasculitis associated with tuberculosis, two had polyarthritis, one polymyalgia rheumatica and one giant cell arteritis. Six sera were ANCA-positive with perinuclear pattern in four cases, atypical pattern in one and cytoplasmic pattern in one. Two sera had anti-myeloperoxidase (MPO) specificity, and others had no known specificity; none had anti-proteinase 3 (PR3) specificity. Global prevalence of ANCA in our cohort was 3%, similar to the French general population.
Polyarteritis nodosa-type systemic vasculitis and polymyalgia rheumatica were the most frequent findings (18%) in myelodysplastic syndromes and particularly in chronic myelomonocytic leukaemia. ANCA were not helpful for the diagnosis of vasculitis. Vasculitis associated with infection, in particular tuberculosis, must be ruled out.
Two cases of systemic antineutrophil cytoplasmic antibody (ANCA) vasculitis in the setting of chronic lymphocytic leukaemia and angioimmunoblastic lymphadenopathy type T cell lymphoma are reported. The two patients had fever of unknown origin associated with cutaneous vasculitis and "pulmonary-renal syndrome" with alveolar haemorrhage. Despite anti-infectious treatments, steroids, and chemotherapy, the vasculitis had a fatal paraneoplastic course in several weeks. When infection is excluded in patients with malignancy, atypical features should be promptly investigated for systemic vasculitis, and an ANCA test performed.
To determine the clinical aspects of systemic vasculitis associated with chronic myelomonocytic leukemia (CMML).
In this retrospective study, 8 patients suffering from systemic vasculitis associated with CMML are described. The French and English literature on systemic vasculitis associated with myelodysplasia was reviewed.
All 8 patients had a systemic medium-sized vessel vasculitis which fulfilled the American College of Rheumatology criteria for polyarteritis nodosa in the setting of active CMML. Antineutrophil cytoplasmic antibodies (ANCA) were negative in 7 patients. One patient had cytoplasmic ANCA by indirect immunofluorescence without antiproteinase 3 or antimyeloperoxydase antibodies on the enzyme-linked immunosorbent assay. At presentation, 6 patients had fever of unknown origin, 5 had polymyalgia rheumatica, 3 had sensory hearing loss, and 4 had eosinophilia. None had viral infection or drug-associated vasculitis. Diagnostic procedures included renal or hepatic angiography in 6 patients which showed microaneurysms in 4, skin and temporal artery biopsy in 2 which showed vasculitis, and 1 postmortem examination which showed gastroduodenal arteritis. All patients were treated with corticosteroids, and 7 received immunosuppressive drugs. Death was attributable to vasculitis in 2 cases, infection in 3, and other vasculitis-related causes in 2. In a review of the French-English literature, we found 11 similar cases of ANCA-negative systemic vasculitis, generally associated with refractory anemia, with or without blast excess.
Systemic ANCA-negative polyarteritis nodosa-type vasculitis seems closely associated to CMML. Clinical presentation is nonspecific, and systemic vasculitis should be suspected when a patient with myelodysplasia develops atypical manifestations. Renal, gastrointestinal, or hepatic angiography are useful diagnostic procedures when more invasive biopsies should be avoided because of low platelet count. The prognosis of CMML-associated systemic vasculitis is poor.
Little is known about the etiologies of diseases associated with circulating antineutrophil cytoplasm autoantibodies (ANCA), such as primary vasculitides and inflammatory bowel diseases. However, the understanding of immune mechanisms supposedly involved in the pathogenesis of these diseases is still growing. In the present review, we first focus on the mechanisms triggering the development of ANCA, including the potential role of microbial superantigens and the possible defect(s) in the progression of apoptosis or in the removal of apoptotic cells. We next concentrate on the contribution of ANCA to the clinical symptoms and on the pathogenic role of ANCA, including the accessibility of ANCA antigens as targets for circulating antibodies and the mode of action of ANCA. Mechanisms of neutrophil activation by ANCA include the engagement of Fcgamma receptors, the possible mechanisms of neutrophil-mediated tissue damage, and the neutrophil-endothelial interaction.
In the light of previous reports of an association between malignancy and renal vasculitis, we aimed to investigate the association of malignancy in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, either Wegener's granulomatosis (WG) or microscopic polyangiitis (MPA), and compare it with the general population and disease control groups comprising patients with systemic lupus erythematosus (SLE) or Henoch-Schonlein purpura (HSP).
A retrospective review of 200 consecutive patients with WG or MPA was performed. Malignancies preceding or concurrent with vasculitis were recorded and the incidence of malignancy was compared with those in a population of 129 patients with HSP, 333 patients with SLE and a normal population in the West Midlands of the UK.
Twenty patients had a diagnosis of malignancy, 14 had MPA and six had WG. Patients with ANCA-associated vasculitis had an increased risk of malignancy compared with HSP patients, of whom six patients had malignancy (relative risk 0.85, confidence interval 0.69-1.05; P = 0.034), or SLE patients, of whom five patients had malignancy (relative risk 0.31, 95% confidence interval 0.14-0.7; P<0.0001). The rate of malignancy compared with an age-matched control group was increased in patients with ANCA-associated vasculitis and HSP (ANCA-associated vasculitis, relative risk 6.02, 95% confidence interval 3.72-9.74; HSP, relative risk 5.25, 95% confidence interval 2.4-11.5). The presence of ANCA was not predictive of malignancy.
In conclusion, patients with ANCA-associated vasculitis have an increased risk of preceding or concurrent malignancy.
Coexistence of a vasculitis and a neoplastic disease is rare and the pathogenesis is unknown. Most of these associations refer to leukocytoclastic or poliarteritis nodosa (PAN)-type vasculitis and hematological malignancies. There are few reports of vasculitis in patients with solid tumours and there are also few reports of paraneoplastic ANCA-associated vasculitis. We report a case of p-ANCA-positive vasculitis with peripheral nerve involvement associated with a colon cancer. Vasculitis resolved after corticoid treatment and surgical removal of the tumour.
Prevalence of rheumatic manifestations and ANCA in haematologic neoplasia. A prospective study
- M A Hamidou
- S Derenne
- M Audrain
- J M Berthelot
- A Boumalassa
- J Y Groleau
Hamidou MA, Derenne S, Audrain M, Berthelot JM, Boumalassa
A, Groleau JY. Prevalence of rheumatic manifestations and ANCA
in haematologic neoplasia. A prospective study. Rheumatology
2000;39:417-20.
The National Cancer Data Base report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia
- Diehl Lf
- Lh
- Menck
- Hr
Diehl LF, Karnell LH, Menck HR. The National Cancer Data Base report on age, gender, treatment, and outcomes of patients with chronic lymphocytic leukemia. Cancer 1999;86:2684–92.
- G S Hoffman
- U Specks
Hoffman GS, Specks U. Antineutrophil cytoplasmic antibodies. Arthritis Rheum 1998;41:1521-37.
Prevalence of rheumatic manifestations and ANCA in haematologic neoplasia. A prospective study
- Hamidou