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Autoimmunity Reviews 7 (2008) 352–358 www.elsevier.com/locate/autrev

Rheumatic disorders as paraneoplastic syndromes ☆ ⁎ Vito Racanelli, Marcella Prete, Carla Minoia, Elvira Favoino, Federico Perosa

Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy Received 22 January 2008; accepted 6 February 2008 Available online 22 February 2008

Abstract

The long-established observation that some rheumatologic disorders (RDs) are associated with – or precede – the clinical manifestations of a variety of solid and hematological tumors represents an important clue for the early diagnosis and effective treatment of the . Inflammatory , seronegative rheumatoid and some atypical vasculitides are the most frequently reported paraneoplastic RDs, although paraneoplastic - and -like syndromes, erythema nodosum, and Raynaud's syndrome have also been observed. Generally, the clinical course of a paraneoplastic RD parallels that of the , and surgical removal of the tumor or its medical treatment usually results in a marked regression of the clinical manifestations of the RD. Most paraneoplastic RDs are difficultly distinguishable from idiopathic RDs. Even so, some atypical features of the clinical presentation raise the suspicion of an underlying tumor. This review summarizes current hypotheses for the pathogenesis that leads a tumor to present as an RD and discusses the clinical features that help distinguish paraneoplastic from idiopathic RDs. © 2008 Elsevier B.V. All rights reserved.

Keywords: Autoimmune ; Cancer; Paraneoplastic rheumatic syndromes

Contents

1. Introduction ...... 353 2. Pathogenetic hypotheses ...... 353 3. Clinical features ...... 353 3.1. Inflammatory myopathies ...... 353 3.2. -like syndrome ...... 354 3.3. Raynaud's phenomenon and scleroderma-like syndrome ...... 355 3.4. Lupus-like syndrome...... 355

☆ This work was supported by grants from the “Associazione Italiana per la Ricerca sul Cancro”, Milan, the Foundation “Cassa di Risparmio di Puglia”, Bari, and the University of Bari Medical School, Bari. ⁎ Corresponding author. Department of Internal Medicine and Clinical Oncology (DIMO), Section of Internal Medicine, University of Bari Medical School, Piazza G. Cesare 11, I-70124, Bari, Italy. Tel.: +39 80 547 88 62; fax: +39 80 547 88 20. E-mail address: [email protected] (F. Perosa).

1568-9972/$ - see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2008.02.001 V. Racanelli et al. / Autoimmunity Reviews 7 (2008) 352–358 353

3.5. ...... 355 3.6. Vasculitides ...... 356 4. Conclusions ...... 357 Acknowledgments ...... 357 Take-home messages ...... 357 References ...... 357

1. Introduction factor, such as a viral infection or exposure to drugs or particular physical stimuli (e.g. UV radiation); The association between cancer and rheumatic b) paraneoplastic RDs are a direct effect of toxins disorders (RDs) is a matter of discussion in view of produced by tumors cells, which trigger in their intriguing relations [1–3]. Patients with both cancer the tissues where RDs manifest; c) paraneoplastic RDs and an RD are distinguished into three main classes. In are mediated by a reaction due either to the first class, an RD is directly triggered by a tumor or its tumoral expression of antigens shared by the cells metastases. An example of this first group is arthritis due targeted by the autoimmune or to the release of to synovial infiltration by leukemic cells. The second intracellular antigens, including nucleic acid-associated class refers to patients with an established idiopathic RD proteins, from apoptotic tumor cells [5]. Supporting this who develop cancer within a temporal interval of up to third hypothesis is the demonstration of auto-antibodies 20 years. Sjögren's syndrome can be such a tumor- to nuclear proteins and to double-stranded DNA as well associated RD, because it places patients at high risk of as antibodies to a wide array of tissue-associated an- developing lymphoma. It is currently unknown whether tigens in the sera of patients with paraneoplastic RDs the higher incidence of cancer in patients with idiopathic [5–8]. The specificities of these antibodies are known RDs is due to the disease itself, the long-term [6,7,9], but their roles as mediators of the clinical mani- immunosuppressive treatment these patients receive, or festations of RDs remain to be established. both [3]. The third group includes patients with clinical manifestations of an RD, which is actually the expres- 3. Clinical features sion of an occult cancer that becomes clinically evident within months or years. These apparently idiopathic RDs That an apparently idiopathic RD can be an early that precede cancer are called paraneoplastic RDs. manifestation of cancer has been known since the first This review focuses on the third group of patients, case report published in 1916 (reviewed in [10]). Since i.e. those with paraneoplastic RDs. It summarizes then, several different types of paraneoplastic RDs have current hypotheses for the pathogenetic mechanisms been described. Clinical presentations may resemble, for that lead a tumor to present as an RD and discusses the example, connective tissue disease, polymyalgia rheu- clinical features that help distinguish paraneoplastic matica or . These diseases are almost indis- from idiopathic RDs. tinguishable from idiopathic RDs. Even so, certain clinical and laboratory findings can raise the suspicion 2. Pathogenetic hypotheses of an underlying malignancy (Table 1).

The main distinguishing feature between tumor- 3.1. Inflammatory myopathies associated and paraneoplastic RDs is the fact that surgical removal or pharmacological treatment of the Estimates for the incidence of cancer in persons with cancer in the first case has no influence on rheumatic an established autoimmune , namely poly- symptoms, whereas it almost always results in the and dermatopolymyositis, range from 6% to disappearance of symptoms in paraneoplastic diseases 60% [26]. In contrast, the incidence of inflammatory (reviewed in [4]). These observations have prompted myopathies that are really the expression of an occult oncologists and rheumatologists to investigate the cancer is undefined. Paraneoplastic inflammatory myo- pathogenetic mechanisms of the rheumatic manifesta- pathies have been observed more often as the early tions of cancer, leading to three distinct working clinical manifestations of ovarian [10], renal [11], lung hypotheses: a) both the malignancy and the paraneo- [11] and colorectal carcinomas (unpublished observa- plastic RD are independent effects of a common causal tions) [11] and melanoma [12]. Following removal of the 354 V. Racanelli et al. / Autoimmunity Reviews 7 (2008) 352–358

Table 1 Atypical characteristics of RDs preceding a hidden malignancy Rheumatic Atypical presentation Response to therapy Underlying malignancy syndrome Age, Symptoms Laboratory Hematological Solid tumors years tumors Inflammatory N50 – , Poor response to Lymphoma, Kidney, ovary, lung, myopathies thrombocytopenia, CS and IS leukemia [4]. gastrointestinal tract , (PM/DPM) hyper-Ig melanoma [10–12]. Rheumatoid N60 Rapid onset; asymmetric No or poor response Acute myeloblastic Lung, colon , breast , arthritis-like arthritis generally absent to DMARDs leukemia, [1]. ovary, stomach, syndrome oropharynx [2]. Raynaud's N50 Asymmetric involvement Thrombocytopenia, Poor response; Lymphoma, Liver, ovary, testis, phenomenon ⁎ of with ANA and ACA, hyper- marked resolution multiple myeloma kidney, melanoma Ig; microhematuria of digital necrosis [2]. [2,19,20]. after tumor treatment Scleroderma-like N50 Acute onset of Raynaud's ANA and anti-Scl70 NA T-cell lymphoma, Stomach, lung, skin, syndrome phenomenon;progressive usually negative osteosclerotic breast [15–18]. sclerosis, myeloma [13,14]. Lupus-like N40 Serositis, Raynaud's ANA positive Normal response Hairy cell leukemia, Ovary, breast, head syndrome ⁎ phenomenon; subacute lymphomas [2,3]. and neck, meningioma cutaneous lupus [2,21,28]. Polymyalgia b50 Asymmetric involvement ESRb40 or ≥100 Poor response to CS Myelodysplastic and Kidney, prostate, rheumatica at typical sites; only one mm/h, severe anemia, myeloproliferative breast, colon, lung, typical site proteinuria syndromes [22]. cavernous hepatic hemangioma [1,4,23–25]. Abbreviations: ACA, anti-centromere antibody; ANA, antinuclear antibodies; CS, corticosteroids; DMARDs, disease-modifying antirheumatic drugs; ESR; erythrocyte sedimentation rate; hyper-Ig, hypergammaglobulinemia; IS, immunosuppressive drugs; NA, not applicable (no therapy); PM/DPM, /dermatopolymyositis. ⁎ Rare associations: only case reports.

cancer, the clinical and biological abnormalities usually of cancer are too small for a specific association to be resolve until the cancer relapses. defined or for specific conclusions to be drawn [1]. The clinical features and laboratory findings of paraneoplastic inflammatory myopathies are generally 3.2. Rheumatoid arthritis-like syndrome similar to those of the idiopathic conditions, although onset in patients older than 50 years and a poor response to An increased occurrence of malignancies in patients immunosuppressive treatment should prompt investiga- with established rheumatoid arthritis (RA) has been tion into a possible underlying malignancy [10].Labora- found by several studies [2,3]. In most cases, the higher tory tests showing occult blood in stool, sideropenic rate of cancer is linked to the use of immunosuppressive anemia, thrombocytopenia and hypergammaglobuline- therapy, and the tumor generally takes several years to mia should also raise the suspicion of an occult neoplasm. develop. However, a rapid-onset arthritis mimicking RA Biomarkers are of limited utility in screening for tumors may be the early manifestation of an occult malignancy. and their sensitivity for an early diagnosis is low [5].Data Patients with paraneoplastic RDs generally exhibit a collected in these patients support the hypothesis that form of asymmetric polyarthritis that may be confused circulating auto-antibodies reactive with tissue proteins with seronegative RA or spondyloarthropathy. The are involved in the pathogenesis of tissue damage [9]. clinical features include: late and acute onset character- Much less is known about the association of other ized by symmetric or asymmetric disease mostly types of inflammatory myopathies (e.g. inclusion body affecting the lower extremities and usually sparing myositis, sine myositis, necrotizing the small joints of the hands; non-specific synovitis myopathy, localized nodular myositis, and myopathies with apparently normal joint radiographs; and frequent with modest increase of muscle enzyme) and an under- lack of rheumatoid factor. In this setting, dispropor- lying malignancy; the numbers of patients with each type tionate pain, marked weight loss, hepatosplenomegaly, V. Racanelli et al. / Autoimmunity Reviews 7 (2008) 352–358 355 lymphadenomegaly, poor response to steroids and association with stomach [15], lung [16], skin [17] and disease-modifying antirheumatic drugs (DMARDs), breast cancer [18] and T-cell lymphoma [13]. Skin particularly if unexplained anemia or constitutional changes resembling scleroderma may also occur in symptoms persist after treatment, should prompt further patients with osteosclerotic myeloma (POEMS syn- investigation [2]. drome) as the early manifestation of cancer [14]. The clinical course of an RA-like syndrome gen- erally parallels that of the cancer. The symptoms often do 3.4. Lupus-like syndrome not respond to antirheumatic therapy, whereas radical treatment of the primary neoplasm usually results in The association between systemic lupus erythema- regression of a paraneoplastic RA [4]. RA-like syndromes tosus and neoplastic diseases is rare and the relation have been associated with malignancies of the lung, between these two pathologies is uncertain [1]. A lupus- colon, breast, ovary, stomach and oropharynx and with like syndrome has been described as the presenting hematopoietic cancers. Often, the RA-like syndrome symptom of ovarian and breast cancer and hairy cell precedes the development of cancer by 8–12 months. leukemia [2,21]; it is characterized by polyserositis, Raynaud's phenomenon and antinuclear antibodies in 3.3. Raynaud's phenomenon and scleroderma-like adult patients. An increased risk of lymphoma has also syndrome been reported [2]. Cases of subacute cutaneous lupus erythematosus associated with meningioma [28] and Both Raynaud's phenomenon and scleroderma-like head–neck cancer [21] have been reported. The syndrome may occasionally be a paraneoplastic RD presence of antinuclear antibodies without clinical [1,4]. Idiopathic Raynaud's phenomenon or Raynauld's signs of rheumatic disease is not predictive of occult phenomenon associated with systemic sclerosis has malignancy [29]. been observed as the expression of an underlying tumor. When Raynaud's phenomenon is observed as an 3.5. Polymyalgia rheumatica isolated symptom, suspicion of an underlying malig- nancy should be raised if the age at onset exceeds Polymyalgia rheumatica, a relatively common dis- 50 years, if asymmetric involvement of the fingers ease in the elderly, is characterized by discomfort and rapidly evolves to necrosis, and if there is a poor stiffness of the shoulders and girdle, fatigue, anemia of response to vasodilator therapy and sympathectomy chronic disease, and elevated erythrocyte sedimentation [4,11]. As observed for other paraneoplastic RDs, once rate. While the relationship between polymyalgia the tumor has been identified and removed, the digital rheumatica and giant cell is well recognized, vasospastic complications markedly resolve. Raynaud's its association with cancer is controversial. For example, phenomenon has been diagnosed as the presenting a prospective study [30] of patients with classic symptom of carcinomas of the liver, ovary, testis, kidney polymyalgia rheumatica found that they do not have and of melanoma, lymphoma, and multiple myeloma. an increased risk of developing cancer, as do patients While several studies (reviewed in [27])have with inflammatory myopathies. Moreover, many dis- demonstrated an increased frequency of lung, esopha- eases, including other RDs and systemic infections, can geal and breast cancer in patients with scleroderma, mimic polymyalgia rheumatica. Nonetheless, Naschitz there are only a few observations of scleroderma-like [4] identified the following atypical features of poly- syndrome preceding the manifestation of cancer. The myalgia rheumatica that can be the expression of an main atypical clinical features that help differentiate underlying malignancy: age b50 years, limited or these forms from idiopathic conditions are: age at onset asymmetric involvement of typical sites, an erythrocyte over 50 years, sclerodactyly, progressive skin sclerosis sedimentation rate less than 40 or higher than 100 mm/h, extending to the neck and trunk, and acute onset of poor or incomplete response to low doses of corticos- Raynaud's phenomenon. By contrast, the absence of teroids, and long-lasting symptoms. All the seven Raynaud's phenomenon with a normal capillaroscopy patients examined by Naschitz and coworkers were pattern can be another distinguishing feature of cancer- found to have metastatic tumors. induced systemic sclerosis. Rarely, high serum titers of Myelodysplastic syndromes and myeloproliferative antinuclear antibodies and anti-topoisomerase type 1 syndromes are the malignancies most frequently antibodies can be present in the absence of autoimmune associated with polymyalgia rheumatica [22]. Single disease symptoms. Single case reports of paraneoplastic associations with breast [24], colon [25], kidney and scleroderma-like syndrome have been described in prostate cancer [23] have also been reported [1,4]. 356 V. Racanelli et al. / Autoimmunity Reviews 7 (2008) 352–358

Recently, a benign cavernous hepatic hemangioma has unclear correlation with previous infections or systemic been observed in a 59-year-old patient with polymyalgia autoimmune diseases, a chronic-relapsing course, and rheumatica refractory to conventional therapy; resec- lack of response to conventional treatment are the most tion of the lesion resulted in complete resolution of the suspicious findings suggestive of a hidden malignancy, RD [2]. besides weight loss and a decline in general health. Increased erythrocyte sedimentation rate, anemia and 3.6. Vasculitides leukopenia are additional factors that should strengthen the suspicion of a coexistent tumor. Auto-antibodies, A number of vasculitic syndromes are occasionally immune complexes and complement consumption are associated with malignancies (Table 2). The incidence of typically absent. malignancies in patients with vasculitides has been Erythema nodosum is a form of panniculitis frequently estimated to be 8% [1]. Cutaneous leukocytoclastic seen in clinical practice. It may be idiopathic or secondary vasculitides are the most frequent paraneoplastic types to numerous causes, including exposure to drugs, and, importantly, clinical manifestations of skin involve- infection, systemic diseases, and malignancies. The ment usually appear before or concurrent with the appearance, histological nature, and distribution of the diagnosis or relapse of a tumor [31]. The most frequent skin lesions in paraneoplastic erythema nodosum are types of cancer that develop in patients with vasculitis indistinguishable from those in the idiopathic condition are lymphoproliferative disorders and myelodysplastic and in secondary forms due to non-cancer causes. syndromes; solid neoplasms are less common [31,32]. However, paraneoplastic erythema nodosum is distin- The of paraneoplastic vasculi- guished by its poor response to conventional treatment. tides are similar to those in patients who do not have an Patients with relapsing or treatment-resistant erythema underlying cancer. Nevertheless, the age at diagnosis, an nodosum that lasts 6–12 months or more should be

Table 2 Atypical characteristic of vasculitides preceding a hidden malignancy Atypical vasculitis Atypical presentation Interval from onset Underlying malignancy to malignancy Age, Symptoms Laboratory Hematological Solid tumors years tumors Cutaneous N50 Chronic relapsing ESR markedly Months to 3 years Lymphomas, Hepatocarcinoma, kidney, leukocytoclastic course high, anemia myelodysplastic colon, head/neck and vasculitis syndromes [31] endometrial [32] Polyarteritis N60 Skin involvement ANA and RF Months to 2 years Multiple myeloma, Gastric, lung angiomatoid nodosa (100%) slightly positive non-Hodgkin's fibrous histiocytoma [34]. lymphoma [33] Henoch–Schönlein N40 Severe renal Anemia 1 year Multiple myeloma [31] NSCLC, prostate, breast, purpura involvement and kidney [31]. arthralgias Chronic erythema N60 Relapsing course – Months Lymphomas, – nodosum myelodysplastic syndromes [35] Churg–Strauss 40–60 – High ESR, Months Non-Hodgkin's l – syndrome eosinophilia, ymphomas [36] hyper-Ig ANCA-associated N40 ––1–3 months – Kidney, colon [11,37]. vasculitis Giant cell N60 – Elevated 3–5 months Myelodysplastic Gastrointestinal tumors [38]. arteritis inflammatory syndromes, acute markers myeloid leukemia [22,38] Takayasu's 20–50 – High CA-125 2 months – Ovarian carcinoma [39]. arteritis Behçet's N60 ––Years Lymphomas, Bladder, breast, uterus, syndrome leukemia [40] and stomach [40]. Abbreviations: ANA, antinuclear antibodies; ANCA, anti-neutrophil cytoplasmic antibodies; CA-125, cancer antigen 125; ESR, erythrocyte sedimentation rate; hyper-Ig, hypergammaglobulinemia; NSCLC, non-small cell lung cancer; RF, rheumatoid factor. V. Racanelli et al. / Autoimmunity Reviews 7 (2008) 352–358 357 investigated for occult cancer [4]. In these patients, the Take-home messages skin lesions may antedate the symptoms of cancer by several months. Paraneoplastic erythema nodosum has • Several apparently idiopathic rheumatic diseases can been observed in patients with hematological malignan- be early manifestations of hidden cancer. cies (lymphoma, myelodysplastic syndromes) and only • Atypical clinical and laboratory features of these rarely in patients with solid tumors (reviewed in [11]). rheumatic diseases aid in the diagnosis. Less commonly associated with tumors are systemic • Recognition of a paraneoplastic rheumatic disease vasculitides such as polyarteritis nodosa, Henoch– may permit early diagnosis and more effective Schönlein purpura, giant cell arteritis, Takayasu's ar- treatment of the cancer. teritis, Behçet's syndrome and anti-neutrophil cytoplas- • Current evidence is from single case reports and mic antibody (ANCA)-positive vasculitis (Table 2). small studies; to improve the evidence base in this area, international reference centers that system- 4. Conclusions atically collect data could be established. • Diagnostic procedures and criteria should be devel- There is increasing recognition that tumors may be oped to guide physicians considering the need for associated with a wide range of rheumatic disorders further, often expensive, investigations for a hidden (RDs). The etiology of paraneoplastic RDs is often cancer. unknown and the pathogenesis of this association remains to be determined. 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Elimination of antigen-presenting cells and autoreactive T cells by Fas contributes to prevention of autoimmunity

Fas (also known as Apo-1 and CD95) receptor has been suggested to control T cell expansion by triggering T cell- autonomous apoptosis. This paradigm is based on the extensive lymphoproliferation and systemic autoimmunity in mice and humans lacking Fas or its ligand. However, with systemic loss of Fas, it is unclear whether T cell- extrinsic mechanisms contribute to autoimmunity. In this study, Stranges PB. et al. (Immunity 2007; 26: 629-41) found that tissue-specific deletion of Fas in mouse antigen-presenting cells (APCs) was sufficient to cause systemic autoimmunity, implying that normally APCs are destroyed during immune responses via a Fas-mediated mechanisms. Fas expression by APCs was increased by exposure to microbial stimuli. Analysis of mice with Fas loss restricted to T cells revealed that Fas indeed controls autoimmune T cells, but not T cells responding to strong antigenic stimulation. Thus, Fas-dependent elimination of APCs is a major regulatory mechanism curbing autoimmune responses and acts in concert with Fas-mediated regulation of chronically activated autoimmune T cells.