Rheumatic paraneoplastic syndromes – A clinical link between malignancy and autoimmunity

Accepted Manuscript Rheumatic paraneoplastic syndromes – A clinical link between malignancy and autoimmunity

Bernhard Manger, Georg Schett PII: DOI: Reference:

S1521-6616(17)30527-2 doi: 10.1016/j.clim.2017.07.021 YCLIM 7899

To appear in:

Clinical Immunology

Received date: Accepted date:

13 July 2017 19 July 2017

Please cite this article as: Bernhard Manger, Georg Schett , Rheumatic paraneoplastic syndromes – A clinical link between malignancy and autoimmunity. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Yclim(2017), doi: 10.1016/j.clim.2017.07.021

This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT Rheumatic paraneoplastic syndromes – a clinical link between malignancy and autoimmunity Bernhard Manger, Georg Schett

AC C

EP T

ED

MA

NU

SC

RI

PT

Department of Internal Medicine 3 – Rheumatology and Immunology, Friedrich-AlexanderUniversity Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen

ACCEPTED MANUSCRIPT

Abstract

AC C

EP T

ED

MA

NU

SC

RI

PT

Paraneoplastic syndromes are rare but can have enormous clinical impact on diagnosis and outcome of neoplastic diseases. The rheumatologist should be familiar with a few typical musculoskeletal manifestations of malignancies to be able to diagnose them early for a timely initiation of anti-tumour therapies. This review describes the characteristic features of various paraneoplastic arthritides and vasculitides, cancer-associated myositis, hypertrophic osteoarthropathy, and tumour-induced osteomalacia. In addition, the current knowledge about underlying pathomechanisms of these syndromes is discussed.

ACCEPTED MANUSCRIPT

Introduction

RI

PT

Rheumatic symptoms can be related to malignant diseases in various ways. Tumours can arise from mesenchymal cells in bone, cartilage, muscles, or connective tissues, or the musculoskeletal system can become invaded by metastatic spreading of tumours from other locations or infiltrated by hematolymphatic malignancies [1,2]. In addition, some tumour therapies can induce a multitude of rheumatic manifestations. Of particular interest to the rheumatologist are musculoskeletal symptoms caused by aromatase-inhibitors [3], BCGinduced reactive arthritis in urinary bladder carcinoma [4], and most recently various autoimmune phenomena and symptoms after treatment with immune checkpoint inhibitors [5]. This review is intended to focus on a third possible mechanism that connects malignant cell growth and autoimmunity: paraneoplastic rheumatism.

NU

SC

Paraneoplastic syndromes are rare but have characteristic features, which can be of utmost clinical importance for an early detection and therapy of an occult malignancy. They are not directly caused by the tumour itself or its metastases but are mediated by soluble factors, such as hormones and cytokines, or humoral or cellular immune mechanisms against tumour cells. Therefore, the clinical manifestation of paraneoplastic syndromes occurs distant from the underlying malignancy and can involve joints, fasciae, muscles, vessels, and bones [6,7].

EP T

ED

MA

To classify a rheumatic disease as truly paraneoplastic, a causal relationship between the malignant disease and the musculoskeletal pathology has to be demonstrated. For the argument of causality over mere coincidence, a set of criteria has been proposed more than 50 years ago, called the Bradford Hill Criteria [8]. In the case of paraneoplasias, besides strength and specificity of an association between tumour diagnosis and rheumatic symptoms, their temporal relationship is the main critical issue. A syndrome is generally considered paraneoplastic, when its musculoskeletal manifestations appear either simultaneously or no longer than one year, in some studies up to two years, before the detection of the malignancy. The best evidence for causation is established in retrospect, when it is possible to completely eliminate a tumour and the rheumatic symptoms undergo full remission [9].

AC C

Based on these considerations, an overview will be given about the clinical characteristics and current pathophysiological understanding of various forms of paraneoplastic polyarthritis (PA), cancer-associated myositis (CAM), paraneoplastic vasculitis, hypertrophic osteoarthropathy (HOA), and tumour-induced osteomalacia (TIO). For other rheumatic disorders such as polymyalgia rheumatica or adult-onset Still´s disease, the potential association to an underlying malignancy was felt not to be strong enough to list them as true paraneoplasias [10,11]. Paraneoplastic arthritis (PA) In the past, numerous case reports and small case series have been reported, in which the de novo manifestation of a highly inflammatory synovitis preceded or led to the detection of an underlying malignant tumour. The largest cohort of 65 patients with PA has recently been described and their clinical and demographic characteristics were compared to those of 50 patients with a new onset of rheumatoid arthritis (RA). The mean age of onset in paraneoplastic arthritis is 50, a male preponderance of 65% stands in sharp contrast to RA. The synovitis usually starts as acute asymmetric (91%) poly- (34%), oligo- (48%), or monoarthritis (18%) with highly elevated laboratory markers of inflammation. A diagnostic

ACCEPTED MANUSCRIPT

SC

Palmar fasciitis and polyarthritis syndrome (PFPAS)

RI

PT

dilemma in PA arises by the fact that 23% of these patients test positive for rheumatoid factors and 11% for antibodies against anti-citrullinated proteins [12]. Therefore, in individual cases the diagnosis is difficult and often the only clinical hint to search for an underlying malignancy remains a somewhat atypical clinical joint involvement and a poor response to standard anti-rheumatic therapies, especially corticosteroids. So far, no consistent theory has been put forward to explain the pathogenesis. Only in one case of renal cancer, T cells clones with identical receptor rearrangements could be identified in tumour-infiltrating and synovial tissues, suggesting a cross-reactivity of malignant cells and synovial antigens in PA [13]. Recently, citrullinated vimentin has been recognized as an important tumour antigen in epithelial cancers. Also T cell mediated immune responses against citrullinated vimentin expressing cancer cells have been defined, which trigger anti-tumour responses [14]. Hence at least some forms of PA, especially those with antibody responses against citrullinated proteins may be based on immune responses against citrullinated tumour antigens.

AC C

EP T

ED

MA

NU

Recognizing a potential paraneoplasia in a patient presenting with arthritis as is much easier, when in addition to mere synovitis other characteristic features are present. This is the case in PFPAS, where inflammation of palmar and/or plantar fasciae leads to a very distinctive clinical presentation. PFPAS is characterised by a symmetrical acute, diffuse, painful swelling of both hands caused by polyarthritis of finger and wrists in combination with palmar fasciitis. This syndrome presents with a marked thickening and induration of palmar tissues and rapidly progressing flexion contractures (Fig. 1). The palpatory findings are best described by the term “woody hands”. Arthritis of other joints can be present, but is usually milder; plantar involvement occurs in about 20%. Overall about one hundred case reports of this paraneoplastic syndrome can be found in the literature with more than half of them in association with ovarian adenocarcinoma or other tumours of urogenital organs. Frequently, tumour markers such as CA125 or CA19-9 are positive and a diagnostic clue [15,16]. The pathogenetic mechanisms of PFPAS have not been resolved, however, a potential role of connective tissue growth factor (CTGF) has repeatedly been proposed [17,18]. In addition, there exists one anecdotal report about the induction of PFPAS by treatment with a metalloprotease inhibitor [19].

Remitting seronegative symmetrical synovitis with pitting edema (RS3PE) This elderly-onset arthritis, characterised by symmetrical edematous swelling of the dorsum of hands and feet, usually shows an excellent response to corticosteroids and overall good prognosis. However, in pooled data from various European and American studies the malignancy rate was estimated to be as high as 31% [20]. In a Japanese cohort of 33 patients with RS3PE, eight developed cancer within two years after the onset of their arthritis. These patients with tumour had a significant elevation of their serum matrix metalloproteinase 3 levels [21]. In general, in any patient with RS3PE, a poor response to corticosteroids should be considered a red flag and prompt searching for an occult malignancy. Pancreatic panniculitis and polyarthritis (PPP) Polyarthritis in association with a panniculitis resembling erythema nodosum has repeatedly been described in patient with pancreatitis and high levels of serum lipase [21]. The same manifestations can also be seen in acinar cell carcinoma, a subtype of pancreatic cancer,

ACCEPTED MANUSCRIPT which also leads to extremely high concentrations of lipase causes extensive necrotic lesions of subcutaneous fat tissues reaction. The polyarthritis most commonly affects metacarpophalangeal joints. In more than 130 publications, with a dismal prognosis [22].

in the circulation (Fig. 2). This with a surrounding inflammatory ankles, knees, wrists and PPP is consistently associated

Paraneoplastic vasculitis

MA

Cancer-associated myositis (CAM)

NU

SC

RI

PT

Although various vasculitides have been reported in temporal association with malignant diseases, clearly the most prevalent manifestation is cutaneous leukocytoclastic vasculitis [24,25]. Hematologic malignancies are identified as a cause in more than half of the cases with myelodysplasia and non-Hodgkin lymphoma being the most frequent diagnoses [26,27]. Among solid tumours, lung, breast, and urogenital cancer are the most common causes of paraneoplastic vasculitis [25,28]. In a recent retrospective analysis of 421 adult patients presenting with clinically unequivocal or biopsy confirmed cutaneous vasculitis, 16 (3.8%) were paraneoplastic (9 hematologic, 7 solid malignancies). Four had additional joint symptoms and two each had gastrointestinal involvement or nephropathy [29]. In this context it is of interest that especially in adult patients with histology-proven Henoch-Schönlein purpura, malignancies have repeatedly been diagnosed and a deposition of immune complexes containing tumour antigens and IgA is proposed as possible pathogenetic mechanism [30-32].

AC C

EP T

ED

Numerous epidemiologic studies have analysed the relationship between inflammatory muscle diseases and malignancy. A meta-analysis confirmed that dermatomyositis is associated with an underlying neoplastic disease in about 24% of all cases. The overall standard incidence ratios (SIR) range from 3.8 to 7.7. For polymyositis, the association is much weaker (SIR 1.7 to 2.2) and when clinical features of overlap with other collagen vascular diseases are present (e. g. interstitial lung involvement, Raynaud´s phenomenon) tumour risk is not increased [33]. Likewise, the presence of various autoantibodies suggestive for connective tissue disease (such as anti-synthetase, anti-Ro52 or systemic sclerosis associated antibodies) decreases the risk for CAM [34]. However, there is one type of autoantibody clearly associated with CAM. Serum autoantibodies against a 155 kDa intracellular protein (anti-p155) were initially described in juvenile dermatomyositis, but is also found in one out of six adult patients with dermatomyositis. From those adult anti-p155 positive patients, 65% developed a malignant disease within three years after the onset of myositis [35]. This association was confirmed in a number of other myositis cohorts [36]. Subsequently the p155 autoantigen was identified as transcription intermediary factor (TIF)1γ, a member of a protein family involved in various functions (ubiquitination of p53 tumour suppressor gene, apoptosis) linked to carcinogenesis [35]. Thus, an anti-tumour immune response could lead to generation of antibodies against TIF-1γ and contribute to the pathogenesis of CAM by crossreactivity against muscular tissue antigens. Yet another autoantibody (anti-MJ), which binds the nuclear matrix protein NXP2, has been described in patients with CAM, but here the number of patients is still too small to draw firm conclusions [37,38]. Hypertrophic (pulmonary) Osteoarthropathy (HOA) HOA or Marie-Bamberger syndrome represents the classical musculoskeletal paraneoplasia and has frequently been described and reviewed in the rheumatologic literature. It is

ACCEPTED MANUSCRIPT

PT

characterized by two distinctive symptoms: One is the clubbing of distal phalanges of fingers and/or toes, the other an inflammatory, proliferative periostitis causing bone and joint pain and occasionally even synovitis and effusion [39-42]. The predominant locations are tibia and fibula, knees and ankles (Fig. 3). This periostal inflammation causes osteoblast activation, which is easily detectable by increased tracer uptake in bone scans and lamellar ossification of the periosteum along tubular bones in conventional radiography. In retrospective analyses the frequency of HOA in primary lung cancer was close to 1%, however, HOA can also occur occasionally in other types of (mainly intrathoracic) malignancies [42-44]. Because of the characteristic acral fibroblast and periostal osteoblast activation, this syndrome was initially thought to be a variant of acromegaly. Today it has become clear that platelet derived growth factor (PDGF) or vascular endothelial growth factor (VEGF) produced by tumour cells can both contribute to the pathogenesis of HOA [45,46].

RI

Tumour-induced osteomalacia (TIO)

ED

MA

NU

SC

TIO is clinically undistinguishable from other forms of osteomalacia with progressive bone pain, spontaneous fractures, muscle weakness, and fatigue. The biochemical pattern consists of hypophosphatemia, hyperphosphaturia, normal calcium and parathyroid hormone, normal to low levels of calcitriol, and an increased alkaline phosphatase. The reason for the imbalance in phosphate-calcium metabolism is marked renal phosphate wasting, due to high concentrations of circulating fibroblast growth factor 23 (FGF23, phosphatonin). FGF23 inhibits the reabsorption of phosphate in the proximal tubule and suppresses osteoblast differentiation and matrix mineralization in the bone [47]. In the majority of cases, FGF23 is produced by a mesenchymal tumour (mixed connective tissue variant), with other histologies (hemangiopericytoma, giant cell tumour, osteosarcoma) being considerably less frequent [48]. From over 300 cases of TIO, an intraosseous tumour was demonstrated in 40%, in 55% the neoplasm was found in the soft tissue. Only 8% of the tumours were malignant [49]. A successful localization and removal of the neoplasm usually results in a complete recovery from all symptoms.

EP T

Conclusion

AC C

Musculoskeletal paraneoplasias are of clinical importance for a number of reasons: They often precede other clinical manifestations of neoplasms and can facilitate timely diagnosis and potential cure of a malignant disease. After successful elimination of all malignant cells, paraneoplastic symptoms usually subside, but reappearance of musculoskeletal symptoms can indicate a relapse or metastatic spreading, although clinically this is not a reliable phenomenon. Paraneoplastic symptoms can also have significant impact on quality of life, morbidity, and mortality of tumour patients. In recent years, some of the underlying mechanisms of paraneoplastic syndromes have been elucidated improving our understanding of the pathogenesis of rheumatic as well as neoplastic diseases. Conflict of interests The authors declare no competing interests.

References

ACCEPTED MANUSCRIPT [1] Trieu J, Sinnathamby M, Di Bella C, Pianta M, Perera W, Slavin JL, Schlicht SM, Choong PF. Biopsy and the diagnostic evaluation of musculoskeletal tumours: critical but often missed in the 21st century. ANZ J Surg. 2016 Mar;86(3):133-8. [2] Brix N, Rosthøj S, Herlin T, Hasle H. Arthritis as presenting manifestation of acute lymphoblastic leukaemia in children. Arch Dis Child. 2015 Sep;100(9):821-5.

PT

[3] Singer O, Cigler T, Moore AB, Levine AB, Hentel K, Belfi L, Do HT, Mandl LA. Defining the aromatase inhibitor musculoskeletal syndrome: a prospective study. Arthritis Care Res (Hoboken). 2012 Dec;64(12):1910-8.

RI

[4] Tinazzi E, Ficarra V, Simeoni S, Artibani W, Lunardi C. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: a systematic review. Rheumatol Int. 2006 Apr;26(6):481-8.

SC

[5] Suarez-Almazor ME, Kim ST, Abdel-Wahab N, Diab A. Review: Immune-Related Adverse Events With Use of Checkpoint Inhibitors for Immunotherapy of Cancer. Arthritis Rheumatol. 2017 Apr;69(4):687-699.

NU

[6] Manger B, Schett G. Paraneoplastic syndromes in rheumatology. Nat Rev Rheumatol. 2014 Nov;10(11):662-70.

MA

[7] Azar L, Khasnis A. Paraneoplastic rheumatologic syndromes. Curr Opin Rheumatol. 2013 Jan;25(1):44-9.

ED

[8] Hill AB. The environment and disease: association or causation? 1965. J R Soc Med. 2015 Jan;108(1):32-7.

EP T

[9] Naschitz JE, Rosner I. Musculoskeletal syndromes associated with malignancy (excluding hypertrophic osteoarthropathy). Curr Opin Rheumatol. 2008 Jan;20(1):100-5.

AC C

[10] Ungprasert P, Sanguankeo A, Upala S, Knight EL. Risk of malignancy in patients with giant cell arteritis and polymyalgia rheumatica: a systematic review and meta-analysis. Semin Arthritis Rheum. 2014 Dec;44(3):366-70. [11] Hofheinz K, Schett G, Manger B. Adult onset Still's disease associated with malignancy-Cause or coincidence? Semin Arthritis Rheum. 2016 Apr;45(5):621-6. [12] Kisacik B, Onat AM, Kasifoglu T, Pehlivan Y, Pamuk ON, Dalkilic E, Donmez S, Bilge SY, Yilmaz S, Erdem H, Mercan R, Ozturk MA, Bes C, Soy M, Erten S, Cobankara V, Senel S, Oner FA, Direskeneli H, Yilmaz S, Yazici A, Emmungil H, Aksu K, Kul S, Cetin GY, Sayarlioglu M. Diagnostic dilemma of paraneoplastic arthritis: case series. Int J Rheum Dis. 2014 Jul;17(6):640-5. [13] Schultz H, Krenn V, Tony HP. Oligoarthritis mediated by tumor-specific T lymphocytes in renal-cell carcinoma. N Engl J Med. 1999 Jul 22;341(4):290-1. [14] Brentville VA, Metheringham RL, Gunn B, Symonds P, Daniels I, Gijon M, Cook K, Xue W, Durrant LG. Citrullinated Vimentin Presented on MHC-II in Tumor Cells Is a Target for CD4+ T-Cell-Mediated Antitumor Immunity. 2016 Feb 1;76(3):548-60.

ACCEPTED MANUSCRIPT [15] Medsger TA, Dixon JA, Garwood VF. Palmar fasciitis and polyarthritis associated with ovarian carcinoma. Ann Intern Med. 1982 Apr;96(4):424-31. [16] Manger B, Schett G. Palmar fasciitis and polyarthritis syndrome-systematic literature review of 100 cases. Semin Arthritis Rheum. 2014 Aug;44(1):105-11. [17] Yogarajah M, Soh J, Lord B, Goddard N, Stratton R. Palmar fasciitis and polyarthritis syndrome: a sign of ovarian malignancy. J R Soc Med. 2008 Sep;101(9):473-5.

PT

[18] Clarke LL, Kennedy CT, Hollingworth P. Palmar fasciitis and polyarthritis syndrome associated with transitional cell carcinoma of the bladder. J Am Acad Dermatol. 2011 Jun;64(6):1159-63.

SC

RI

[19] Virik K, Lynch KP, Harper P. Gastroesophageal cancer, palmar fasciitis and a matrix metalloproteinase inhibitor. Intern Med J. 2002 Jan-Feb;32(1-2):50-1. [20] Li H, Altman RD, Yao Q. RS3PE: Clinical and Research Development. Curr Rheumatol Rep. 2015 Aug;17(8):49.

MA

NU

[21] Origuchi T, Arima K, Kawashiri SY, Tamai M, Yamasaki S, Nakamura H, Tsukada T, Aramaki T, Furuyama M, Miyashita T, Kawabe Y, Iwanaga N, Terada K, Ueki Y, Fukuda T, Eguchi K, Kawakami A. High serum matrix metalloproteinase 3 is characteristic of patients with paraneoplastic remitting seronegative symmetrical synovitis with pitting edema syndrome. Mod Rheumatol. 2012 Aug;22(4):584-8.

ED

[22] Narváez J, Bianchi MM, Santo P, de la Fuente D, Ríos-Rodriguez V, Bolao F, Narváez JA, Nolla JM. Pancreatitis, panniculitis, and polyarthritis. Semin Arthritis Rheum. 2010 Apr;39(5):417-23.

EP T

[23] Zundler S, Erber R, Agaimy A, Hartmann A, Kiesewetter F, Strobel D, Neurath MF, Wildner D. Pancreatic panniculitis in a patient with pancreatic-type acinar cell carcinoma of the liver--case report and review of literature. BMC Cancer. 2016 Feb 20;16:130.

AC C

[24] Greer JM, Longley S, Edwards NL, Elfenbein GJ, Panush RS. Vasculitis associated with malignancy. Experience with 13 patients and literature review. Medicine (Baltimo re). 1988 Jul;67(4):220-30. [25] Solans-Laqué R, Bosch-Gil JA, Pérez-Bocanegra C, Selva-O'Callaghan A, SimeónAznar CP, Vilardell-Tarres M. Paraneoplastic vasculitis in patients with solid tumors: report of 15 cases. J Rheumatol. 2008 Feb;35(2):294-304. [26] Fain O, Hamidou M, Cacoub P, Godeau B, Wechsler B, Pariès J, Stirnemann J, Morin AS, Gatfosse M, Hanslik T, Belmatoug N, Blétry O, Cevallos R, Delevaux I, Fisher E, Hayem G, Kaplan G, Le Hello C, Mouthon L, Larroche C, Lemaire V, Piette AM, Piette JC, Ponge T, Puechal X, Rossert J, Sarrot-Reynauld F, Sicard D, Ziza JM, Kahn MF, Guillevin L. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum. 2007 Dec 15;57(8):1473-80. [27] de Hollanda A, Beucher A, Henrion D, Ghali A, Lavigne C, Lévesque H, Hamidou M, Subra JF, Ifrah N, Belizna C. Systemic and immune manifestations in myelodysplasia: a multicenter retrospective study. Arthritis Care Res (Hoboken). 2011 Aug;63(8):1188-94.

ACCEPTED MANUSCRIPT

[28] Podjasek JO1, Wetter DA, Pittelkow MR, Wada DA. Cutaneous small-vessel vasculitis associated with solid organ malignancies: the Mayo Clinic experience, 1996 to 2009. J Am Acad Dermatol. 2012 Feb;66(2):e55-65.

PT

[29] Loricera J, Calvo-Río V, Ortiz-Sanjuán F, González-López MA, Fernández-Llaca H, Rueda-Gotor J, Gonzalez-Vela MC, Alvarez L, Mata C, González-Lamuño D, MartínezTaboada VM, González-Gay MA, Blanco R. The spectrum of paraneoplastic cutaneous vasculitis in a defined population: incidence and clinical features. Medicine (Baltimore). 2013 Nov;92(6):331-43.

RI

[30] Pertuiset E, Lioté F, Launay-Russ E, Kemiche F, Cerf-Payrastre I, Chesneau AM. Adult Henoch-Schönlein purpura associated with malignancy. Semin Arthritis Rheum. 2000 Jun;29(6):360-7.

SC

[31] Zurada JM, Ward KM, Grossman ME. Henoch-Schönlein purpura associated with malignancy in adults. Am Acad Dermatol. 2006 Nov;55(5 Suppl):S65-70.

NU

[32] Podjasek JO, Wetter DA, Pittelkow MR, Wada DA. Henoch-Schönlein purpura associated with solid-organ malignancies: three case reports and a literature review. Acta Derm Venereol. 2012 Jul;92(4):388-92.

MA

[33] Zahr ZA, Baer AN. Malignancy in myositis. Curr Rheumatol Rep. 2011 Jun;13(3):208-15.

EP T

ED

[34] Troyanov Y, Targoff IN, Payette MP, Raynauld JP, Chartier S, Goulet JR, BourréTessier J, Rich E, Grodzicky T, Fritzler MJ, Joyal F, Koenig M, Senécal JL. Redefining dermatomyositis: a description of new diagnostic criteria that differentiate pure dermatomyositis from overlap myositis with dermatomyositis features. Medicine (Baltimore). 2014 Nov;93(24):318-32.

AC C

[35] Fujimoto M, Hamaguchi Y, Kaji K, Matsushita T, Ichimura Y, Kodera M, Ishiguro N, Ueda-Hayakawa I, Asano Y, Ogawa F, Fujikawa K, Miyagi T, Mabuchi E, Hirose K, Akimoto N, Hatta N, Tsutsui K, Higashi A, Igarashi A, Seishima M, Hasegawa M, Takehara K. Myositis-specific anti-155/140 autoantibodies target transcription intermediary factor 1 family proteins. Arthritis Rheum. 2012 Feb;64(2):513-22. [36] Trallero-Araguás E, Rodrigo-Pendás JÁ, Selva-O'Callaghan A, Martínez-Gómez X, Bosch X, Labrador-Horrillo M, Grau-Junyent JM, Vilardell-Tarrés M. Usefulness of antip155 autoantibody for diagnosing cancer-associated dermatomyositis: a systematic review and meta-analysis. Arthritis Rheum. 2012 Feb;64(2):523-32. [37] Ichimura Y, Matsushita T, Hamaguchi Y, Kaji K, Hasegawa M, Tanino Y, Inokoshi Y, Kawai K, Kanekura T, Habuchi M, Igarashi A, Sogame R, Hashimoto T, Koga T, Nishino A, Ishiguro N, Sugimoto N, Aoki R, Ando N, Abe T, Kanda T, Kuwana M, Takehara K, Fujimoto M. Anti-NXP2 autoantibodies in adult patients with idiopathic inflammatory myopathies: possible association with malignancy. Ann Rheum Dis. 2012 May;71(5):710-3. [38] Fiorentino DF, Chung LS, Christopher-Stine L, Zaba L, Li S, Mammen AL, Rosen A, Casciola-Rosen L. Most patients with cancer-associated dermatomyositis have antibodies to

ACCEPTED MANUSCRIPT nuclear matrix protein NXP-2 or transcription intermediary factor 1γ. Arthritis Rheum. 2013 Nov;65(11):2954-62. [39] Schumacher HR Jr. Articular manifestations of hypertrophic pulmonary osteoarthropathy in bronchogenic carcinoma. Arthritis Rheum. 1976 May-Jun;19(3):629-36.

PT

[40] Armstrong DJ, McCausland EM, Wright GD. Hypertrophic pulmonary osteoarthropathy (HPOA) (Pierre Marie-Bamberger syndrome): two cases presenting as acute inflammatory arthritis. Description and review of the literature. Rheumatol Int. 2007 Feb;27(4):399-402.

RI

[41] Manger B, Wacker J, Schmidt D, Kuwert T, Cavallaro A, Schett G. Clinical Images: Hippokrates confirmed by positron emission tomography. Arthritis Rheum. 2011 Apr;63(4):1150.

SC

[42] Manger B, Lindner A, Manger K, Wacker J, Schett G. Hypertrophic osteoarthropathy. Bamberger-Marie disease. Z Rheumatol. 2011 Sep;70(7):554-60.

NU

[43] Izumi M, Takayama K, Yabuuchi H, Abe K, Nakanishi Y. Incidence of hypertrophic pulmonary osteoarthropathy associated with primary lung cancer. Respirology. 2010 Jul;15(5):809-12.

MA

[44] Ito T, Goto K, Yoh K, Niho S, Ohmatsu H, Kubota K, Nagai K, Miyazaki E, Kumamoto T, Nishiwaki Y. Hypertrophic pulmonary osteoarthropathy as a paraneoplastic manifestation of lung cancer. J Thorac Oncol. 2010 Jul;5(7):976-80.

ED

[45] Atkinson S, Fox SB. Vascular endothelial growth factor (VEGF)-A and plateletderived growth factor (PDGF) play a central role in the pathogenesis of digital clubbing. J Pathol. 2004 Jun;203(2):721-8.

EP T

[46] Martinez-Lavin M. Exploring the cause of the most ancient clinical sign of medicine: finger clubbing. Semin Arthritis Rheum. 2007 Jun;36(6):380-5.

AC C

[47] Hautmann AH, Hautmann MG, Kölbl O, Herr W, Fleck M. Tumor-Induced Osteomalacia: an Up-to-Date Review. Curr Rheumatol Rep. 2015 Jun;17(6):512. [48] Folpe AL, Fanburg-Smith JC, Billings SD, Bisceglia M, Bertoni F, Cho JY, Econs MJ, Inwards CY, Jan de Beur SM, Mentzel T, Montgomery E, Michal M, Miettinen M, Mills SE, Reith JD, O'Connell JX, Rosenberg AE, Rubin BP, Sweet DE, Vinh TN, Wold LE, Wehrli BM, White KE, Zaino RJ, Weiss SW. Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature. Am J Surg Pathol. 2004 Jan;28(1):1-30. [49] Jiang Y, Xia WB, Xing XP, Silva BC, Li M, Wang O, Zhang HB, Li F, Jing HL, Zhong DR, Jin J, Gao P, Zhou L, Qi F, Yu W, Bilezikian JP, Meng XW. Tumor-induced osteomalacia: an important cause of adult-onset hypophosphatemic osteomalacia in China: Report of 39 cases and review of the literature. J Bone Miner Res. 2012 Sep;27(9):1967-75.

ACCEPTED MANUSCRIPT Legends to Figures:

Fig. 1: Flexion contracture due to palmar fasciitis in a patient with PFPAS and ovarian carcinoma

Fig. 2: Nodular subcutaneous inflammation in a patient with PPP and acinar cell carcinoma.

AC C

EP T

ED

MA

NU

SC

RI

PT

Fig. 3: 18 F-fluorodeoxyglucose positron emission tomography shows marked tracer uptake along the tibial contour in a patient with HOA and bronchial adenocarcinoma.

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

AC C

EP T

ED

MA

Figure 1

AC C

EP T

ED

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

Figure 2

AC C

Figure 3

EP T

ED

MA

NU

SC

RI

PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT Highlights

PT

RI SC NU MA



ED



EP T



Musculoskeletal paraneoplasias are of clinical importance for a number of reasons: They often precede other clinical manifestations of neoplasms and can facilitate timely diagnosis and potential cure of a malignant disease. After successful elimination of all malignant cells, paraneoplastic symptoms usually subside, but reappearance of musculoskeletal symptoms can indicate a relapse or metastatic spreading, although clinically this is not a reliable phenomenon. Paraneoplastic symptoms can also have significant impact on quality of life, morbidity, and mortality of tumour patients. In recent years, some of the underlying mechanisms of paraneoplastic syndromes have been elucidated improving our understanding of the pathogenesis of rheumatic as well as neoplastic diseases.

AC C

