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Rheumatology and Oncology

An Updated Review of Rheumatic Manifestations of Malignancy and Anti-Neoplastic Therapy
Abie Alias, D.O., Ernesto J. Rodriguez, M.D., Helen E. Bateman, M.D., Ashley G. Sterrett, M.D., and Joanne Valeriano-Marcet, M.D.

Abstract Objective: Review of the literature addressing the rheumatic manifestations of various malignancies as well as of common chemotherapeutic agents. Methods: A literature search was performed to identify key articles regarding the association of rheumatic disease with malignancy. Results: Our review focused on the association of rheumatic disease with malignancy, paraneoplastic syndromes with rheumatic manifestations, and chemotherapeutic agents related to rheumatic syndromes. We have discussed the importance of a newly described autoantibody that may identify patients at risk for malignancy associated myositis. Conclusion: Based on our literature review, recommendations are suggested regarding who and how patients should be screened for malignancy when presenting with various rheumatic symptoms. alignancy can be associated with a number of musculoskeletal manifestations that may be caused by direct tumor invasion into bones and joints, as a paraneoplastic syndrome, and through altered immune surveillance (Table 1). Paraneoplastic syndromes cause manifestations at a site distant from the primary tumor with the clinical course often paralleling that of the tumor. Immune dysregulation can result in malignant transformation of rheumatic disease and has been described as a late complication of rheumatoid arthritis (RA), Sjogrens syndrome, systemic sclerosis, and systemic lupus erythematosus (SLE).
Abie Alias, D.O., Ernesto J. Rodriguez, M.D., Helen E. Bateman, M.D., Ashley G. Sterrett, M.D., and Joanne Valeriano-Marcet, M.D., are in the Department of Rheumatology, University of South Florida, and James A. Haley VA Hospital, Tampa, Florida. Correspondence: Helen E. Bateman, 13000 Bruce B. Downs Blvd, Ofce of Rheumatology, Tampa, Florida 33612; Helen. Bateman@va.gov.

Antineoplastic drugs have been found to cause rheumatic syndromes (Table 2), and conversely, antirheumatic therapy can also induce malignancy. This review focuses on rheumatic manifestations of malignancy as paraneoplastic disorders and also describes the musculoskeletal manifestations of antineoplastic therapy.

Paraneoplastic Rheumatic Syndromes

Paraneoplastic rheumatic disorders are induced by malignancy through hormones, peptides, autocrine and paracrine mediators, antibodies and cytotoxic lymphocytes. Recognition of paraneoplastic disorders may lead to an earlier diagnosis of malignancy. Treatment of the underlying primary neoplasm usually results in regression.1 Carcinomatous Polyarthritis Carcinomatous polyarthritis is a seronegative inammatory arthritis that may precede the diagnosis of malignancy. Features include late age at onset, a rapid presentation of asymmetric oligoarthritis or polyarthritis, predominant involvement of lower extremity joints, absence of rheumatoid factor (RF), and a mildly inammatory synovial uid. There are no distinctive pathologic or radiographic features. The temporal relationship between the onset of carcinomatous polyarthritis and the diagnosis of malignancy is typically less than one year. It is most frequently reported in women with carcinoma of the breast and in men with carcinoma of the lung. The arthritis correlates well with tumor regression and recurrence. The symptoms may respond to glucocorticoids or nonsteroidal anti-inammatory drugs (NSAIDS).2 Hypertrophic Osteoarthropathy Hypertrophic osteoarthropathy (HOA) is characterized by digital clubbing, periosteal proliferation, and an arthropathy ranging from arthralgia to diffuse polyarthritis. This is commonly associated with pulmonary malignancies, with

Alias A, Rodriguez EJ, Bateman HE Sterrett AG, Valeriano-Marcet J. Rheumatology and oncology: an updated review of rheumatic manifestations of malignancy and anti-neoplastic therapy. Bull NYU Hosp Jt Dis. 2012;70(2):109-14.

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Table 1 Rheumatologic Manifestations of Malignancy

Direct tumor invasion into joints Leukemia Lymphoma Multiple myeloma Skeletal metastasis Metastatic carcinomatous arthritis Arthropathies Carcinomatous polyarthritis* Hypertrophic osteoarthropathy* Relapsing seronegative symmetric synovitis with pitting edema* Palmar fasciitis and arthritis* Gout Rheumatoid-arthritis like syndrome Multicentric reticulohistiocytosis Panniculitis-arthritis Muscular Disorder Inammatory myopathies* Lambert-Eaton myasthenic syndrome Vasculitic Syndrome Vasculitis* Cutaneous leukocytoclastic vasculitis presenting after age 50* Atypical polymyalgia rheumatica* Scleroderma and Scleroderma Mimicks Systemic scleroderma Eosinophilic fasciitis Other Erythromelalgia* Raynauds syndrome presenting after age 50 Lupus-like syndrome Sjogren syndrome with monoclonality Antiphospholipid antibody syndrome* Chronic regional pain syndrome Relapsing polychondritis Erythema nodosum lasting more than 6 months
*Discussed in detail.

Table 2 Rheumatic Syndromes Caused by AntiNeoplastic Therapy

Rheumatic Syndrome Raynauds Anti-Neoplastic Therapy Bleomycin Vinblastine Vincristine Cisplatin Bleomycin Graft-versus-host disease Interleukin-2 Aromatase Inhibitors Cisplatin 5-Fluorouracil Cyclophosphamide Methotrexate Tamoxifen Interferon Graft-versus-host disease Aromatase Inhibitors Anti-androgens Bacillus Calmette-Guerin

Skin thickening Arthralgias, myalgias (post-chemo rheumatism)

SLE-like/RA-like syndromes Polymyositis Osteoporosis Reactive Arthritis

symptoms, tend to respond poorly to glucocorticoid therapy, and improve with treatment of the underlying malignancy. Currently, there are no data supporting the cost-effectiveness of screening for underlying malignancy in patients with RS3PE; however, it may be appropriate to screen individuals at high risk and those who fail to respond to therapy. Palmar Fasciitis and Arthritis Palmar fasciitis and polyarthritis syndrome is characterized by progressive bilateral digital contractures, inammatory fasciitis, brosis, and inammatory polyarthritis. The syndrome typically precedes the tumor presentation. It has been described most commonly with ovarian carcinoma but has also been reported with endometrial, gastric, pancreatic, prostate, and breast carcinoma, as well as in chronic lymphocytic leukemia and Hodgkins disease. Cases have also been described without underlying malignancy.1 Steroids, NSAIDs, or hand therapy have little effect; while successful treatment of the underlying tumor can improve symptoms. Women who present with inammatory palmar fasciitis or palmar bromatosis should have a thorough malignancy work-up including gynecologic examination.5 Inammatory Myopathy Inammatory myopathies have been associated with malignancy but are most frequently seen with dermatomyositis (DM) and polymyositis (PM). Hill and associates6 used national databases and found malignancy in approximately 30% of DM and 15% of PM cases, with most malignancies diagnosed within 1 year of the development of myositis. The risk of developing malignancy persisted over 5 years in patients with DM. The most common malignancies identied were ovarian, lung, pancreatic, stomach, bladder, colorectal

resolution of the syndrome after tumor resection. HOA can range from asymptomatic disease to incapacitating bone pain, usually seen in those with aggressive malignancies. Vascular endothelial growth factor has been suggested to play a role in the pathogenesis of HOA.3 Relapsing Seronegative Symmetric Synovitis with Pitting Edema Relapsing seronegative symmetric synovitis with pitting edema (RS3PE) is characterized by involvement of the hands and feet, elevated acute phase reactants, negative RF, and absence of radiographic erosions.4 Yao and colleagues4 performed a literature review from 1985 to 2008 and found 32 case reports of malignancy in RS3PE , including 18 solid tumors, 11 hematologic malignancies, and 3 additional malignancies of unknown sites. The malignancy rate associated with RS3PE was found to be as high as 54%. Patients with malignancy associated RS3PE have more dramatic

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cancers, and non-Hodgkins lymphoma (NHL). Features suggesting malignancy include older age, male gender, rapid onset of skin or muscle symptoms, skin necrosis, and periungual erythema.7 Antisynthetase syndrome is characterized by the presence of antihistidyl tRNA synthetase (Jo-1) antibody, interstitial lung disease (ILD), Raynauds phenomenon, arthralgia/ arthritis and mechanics hands. It is thought to have a negative association with malignancy. However, case reports have shown a positive association with malignancy.8 Chinoy and coworkers 9 found that patients without myositis-specic and myositis-associated autoantibodies, including anti-Jo-1, anti-PM-Scl, anti-U1-RNP, anti-U3-RNP, anti-Ku antibodies, had an increased risk of malignancy. However, the presence of autoantibodies specically directed to the N-terminal fragment of the Mi-2 antigen has an association with malignancy.10 Additionally, the presence of the antibody against 155 kDa and 140 kDa protein (anti-155/140 antibody) has been found to be a signicant risk factor for malignancy associated DM. Given the positive predictive value, the antip155 antibody is useful in detecting occult malignancy in patients with DM but is difcult to obtain in clinical practice.9 Currently, there is no consensus concerning who to screen for malignancy, what type of screening should be done, and how often it should be repeated. We recommend age, gender, and ethnic specic cancer screening, which should begin with careful history and physical including gynecologic examination. Routine laboratory testing should include: complete blood count, erythrocyte sedimentation rate (ESR), routine biochemistry, urinary cytology, and fecal occult blood test. Special testing with tumor markers is more controversial but may be indicated. Imaging such as mammography, computed tomography (CT), and ultrasound of the chest, abdomen, and pelvis should be completed.11 FDG-PET/CT, a single imaging study for diagnosing occult malignancy, was found to be comparable to broad conventional screening but is not yet widely used.12 Vasculitides Vasculitis syndromes may predate, follow, or occur concurrently with malignancy and are more commonly associated with hematologic malignancies. In contrast to a traditional paraneoplastic syndrome, malignancy appears to be a vasculitis-triggering factor characterized by a disassociation of the clinical courses. In his analysis of 60 patients with vasculitis associated with malignancy, Fain and colleagues13 found cutaneous leukocytoclastic vasculitis (LV), polyarteritis nodosa (PAN), Churg-Strauss syndrome, microscopic polyangiitis, Wegeners granulomatosis, and Henoch-Schonlein purpura (HSP) to be triggered by malignancy. Of these, LV (45%) and PAN (36.7%) were most commonly seen. Fain and colleagues also described that investigation for occult malignancy may be needed when the vasculitis becomes chronic, treatment is no longer effective, or the

disease is uncontrollable. Elderly males with HSP and joint involvement were shown to have an increased risk for solid tumors, less often hematologic malignancies, and should be screened for cancer. Tumor relapse or cytologic transformation should be considered when vasculitis develops in a patient being followed for a malignancy.13 There have been conicting data regarding the incidence of malignancy associated with giant cell arteritis (GCA). In their population-based case-control study, Kermani and associates14 indicated that GCA patients had signicantly fewer malignancies prior to the diagnosis as compared with controls. In a population based study, Myklebust and coworkers15 found no differences in frequencies or types of malignant neoplasms between patients with GCA and population controls. However Liozon and colleagues16 reported that 7.4% of patients with GCA were diagnosed with a concurrent malignancy within one year, most commonly solid tumors and hematologic malignancies. Atypical Polymyalgia Rheumatica Patients with classical polymyalgia rheumatica (PMR) have not been shown to have increased frequency of malignancy.15 However, a PMR-like syndrome, with atypical features including age greater than 50 years, limited involvement of only one traditional site, asymmetric involvement, additional painful joints, an ESR of less than 40 or greater than 100 mm/h, and lack of improvement on prednisone 10 mg/day has been shown to be associated with malignancy. Patients with atypical PMR may benet from a workup for malignant involvement of bones and joints.17 Erythromelalgia Erythromelalgia is characterized by recurrent attacks of burning pain and warmth and erythema of the extremities, and it can be associated with myeloproliferative disorders and thrombocythemia. Onset of may be gradual or abrupt, and exacerbated by exercise, heat, or dependency of limbs. Treatment consists of analgesia, such as aspirin, and control of the underlying disease.18 Antiphospholipid Antibodies There is a higher prevalence of antiphospholipid antibodies (aPL) in patients with solid tumors and hematologic malignancy compared to those in the general population. Similarly, there is a higher rate of thromboembolic events in aPL positive cancer patients compared to controls who have the same malignancy without aPL. Manifestations of antiphospholipid syndrome (APS) in patients with malignancy are similar to those in classic APS and catastrophic antiphospholipid syndrome (CAPS).19 There is no consensus on the management of patients with aPL and malignancy. Given the increased risk of thromboembolic events in patients with aPL and malignancy, prophylactic anticoagulation should be considered. In healthy aPL carriers, evaluation for underlying hematologic malignancy

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may be indicated.19 In the case of CAPS, malignancy should be considered as a precipitating factor.20

Rhumatic Complications of Cancer Therapies

Post-Chemotherapy Rheumatism A newly recognized but poorly dened syndrome, postchemotherapy rheumatism is a non-inammatory, migratory, and usually self-limited arthropathy of less than 1 year. Symptoms often develop several weeks to months after completion of chemotherapy and include severe myalgias and morning stiffness. Arthralgias and periarticular swelling typically involve hands, ankles, and knees. Antinuclear antibody and RF are not diagnostic, and radiographs do not usually reveal erosion. Symptoms are best treated conservatively with NSAIDs. Recurrent carcinoma or other inammatory conditions should be excluded.21 Although the underlying pathogenesis of this process is as yet unknown, proposed mechanisms include premature menopause and complications of immune reconstitution after completion of treatment. 22-24 The most frequently associated chemotherapeutics include cyclophosphamide, 5-uorouracil, tamoxifen, methotrexate, and cisplatin.25 While post-chemotherapy rheumatism has been best described in patients treated for breast cancer, it has also been reported in other malignancies including ovarian cancer and non-Hodgkin lymphoma.21 Aromatase Inhibitors and Anti-androgen Therapy The aromatase inhibitors (AIs) are increasingly being used as adjuvant therapy in the management of hormone receptor positive breast cancer. Its use has been associated with an increased risk for musculoskeletal complications such as arthralgias and bone mineral density (BMD) loss. Studies have shown that approximately 47% describe joint symptoms that either develop or worsen within 2 to 3 months of initiating AIs.26 Wrists, hands, and knees are disproportionately affected with associated pain and morning stiffness. The majority of patients describe mild to moderate symptoms; however in one study, 5% of patients reported a marked decline in quality of life necessitating withdrawal from treatment.27 Studies have also shown an increased trend toward osteoarthritic changes in the hands, as well as functional disabilities.28 Markers of inammation are usually normal. The etiology, time course, and treatment for AI-induced arthralgias are not well understood and may be related to estrogen deprivation. Current recommendations include mild analgesics, topical medications, NSAIDs, and regular exercise, but these may not be fully effective. Spontaneous symptom resolution on AI therapy is rare. Discontinuation of therapy or switching to a selective estrogen receptor modulator (SERM), such as tamoxifen, is an alternative in patients with debilitating symptoms and usually alleviates pain within weeks.29 Data from clinical trials of third generation aromatase

inhibitors (anastrozole, letrozole, and exemestane), have shown a modest reduction in BMD, increased bone turnover, and an increased risk of fragility fractures when compared to standard tamoxifen therapy.30 In premenopausal women with breast cancer, hypogonadism develops in at least 63% of patients who receive adjuvant chemotherapy. With ovarian failure, a signicant decline in bone density can be seen within 6 months.31 According to American Society of Clinical Oncology (ASCO) guidelines, postmenopausal women treated with AIs are at increased risk for osteoporosis. Current recommendations include annual surveillance with DXA scans, weightbearing exercise, and initiation of osteoporotic treatment for those with T-scores less than -2.5.32 Other chemotherapeutic agents, including anti-androgens for prostate cancer, may also induce osteoporosis.33 Currently, no medications have been approved for the prevention of chemotherapy-induced bone loss. Bacillus Calmette-Guerin (BCG) Musculoskeletal manifestations have been described in approximately 0.5% to 5% of patients receiving intravesical administration of live attenuated Bacillus Calmette-Guerin (BCG) for supercial bladder cancer. Typical manifestations include bland arthralgias or aseptic arthritis. Although rare, most cases occur after 2 to 4 weeks of BCG therapy and present as an oligoarthritis involving knees and ankles.34 Additional symptoms suggestive of an associated reactive arthritis (ReA) include concomitant urinary tract symptoms, sacroiliitis, dactilytis, keratoconjunctivitis sicca, and signs of ocular inammation. Symptoms typically remit with cessation of BCG therapy, and complete clinical recovery within 6 months. Chronic cases have been described in patients who are HLA-B27 positive. Therapy, with variable response, includes NSAIDs, corticosteroids, hydroxychloroquine, isoniazid, and rifampin.35 Another rare complication of intravesical BCG administration is vertebral osteomyelitis (Potts Disease), which requires 9 to 12 months of anti-tuberculous medications.36 Miscellaneous Cancer Therapies Several other chemotherapeutic agents have been linked with the development of rheumatic manifestations. Raynauds phenomenon, with its characteristic skin color changes and pain in response to cold exposure, has been well described with the use of bleomycin, vinblastine, vincristine, and cisplatin in the treatment of lymphomas and germ cell tumors.37 The proposed mechanisms include direct vascular toxicity leading to endothelial dysfunction versus neurotoxicity causing an aberrant sympathetic arterial vasoconstrictive response.38 Bleomycin has also been associated with the development of a scleroderma-like disease characterized by skin thickening, pulmonary brosis, and Raynauds phenomenon.39 This should be distinguished from scleroderma mimics, which

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can include graft-verses-host disease (GVHD). Unlike primary scleroderma, GVHD skin thickening usually spares the ngers, has a limited distribution, and is not associated with Raynaudss phenomenon. A typical case may occur after bone marrow transplantation.40 Granulocyte and granulocyte-macrophage colony stimulating factors (G-CSF/GM-CSF) used in conjunction with chemotherapy may lead to the development of an acute symmetric inammatory arthropathy. Symptoms often occur within hours or days of treatment with the stimulating factor.41 Cytokine based immunotherapy, such as interferon-alpha (INF-alpha) and interferon-gamma (INF-gamma), used in the treatment of lymphoproliferative malignancies, have been associated with the development of autoimmune disorders such as a lupus-like syndrome.42 Most reported cases have shown a reduction in antibody titers, marked clinical improvement, or remission upon cessation of therapy. Other potential complications of INF therapy include exacerbation of pre-existing hepatitis C virus-related arthritis and the induction of a RA-like symmetric polyarthralgia.42,43 Interleukin-2, used in the treatment of metastatic malignant melanoma and renal cell carcinoma, has been reported to induce the development of psoriatic arthritis, ankylosing spondylitis, RA, ReA, and an inammatory necrotizing myositis, as well as causing exacerbations of pre-existing scleroderma.42,44 Discontinuation of treatment generally leads to symptomatic improvement. Another complication of cancer therapy is PM which has been described in association with graft-versus-host disease. One center reported 12 cases of PM over a 30 year period in patients with chronic GVHD who received allogeneic stem cell transplantation.45

Early diagnosis of malignancy through awareness of these associations can lead to improved patient outcomes. In the case of paraneoplastic syndromes, the severity of symptoms can be used as a guide to the response of tumor therapy, since treating the underlying tumor will often resolve the paraneoplastic features. Additionally, knowledge of the association of rheumatic symptoms with various chemotherapeutic agents is essential to differentiate from primary rheumatic disease. Disclosure Statement
No funding was received for this review and authors do not have any nancial interests. A portion of this review was presented at the American College of Rheumatology Annual Scientic Meeting in November 2010 by Dr. Valeriano-Marcet.

References:
1. Andras C, Csiki Z, Ponyi A, et al. Paraneoplastic rheumatic syndromes. Rheumatol Int. 2006 Mar;26:376-82. 2. Fam AG. Paraneoplastic rheumatic syndromes. Baillieres Best Pract Res Clin Rheumatol. 2000 Sep;14:515-33. 3. Silveira LH, Martinez-Lavin M, Pineda C, et al. Vascular endothelial growth factor and hypertrophic osteoarthropathy. Clin Exp Rheumatol. 2000 Jan-Feb;18:57-62. 4. Yao Q, Su X, Altman RD. Is remitting seronegative symmetrical synovitis with pitting edema (RS3PE) a subset of rheumatoid arthritis? Semin Arthritis Rheum. 2010 Aug;40:89-94. 5. Martorell EA, Murray PM, Peterson JJ, et al. Palmar fasciitis and arthritis syndrome associated with metastatic ovarian carcinoma: a report of four cases. J Hand Surg Am. 2004 Jul;29:654-60. 6. Hill CL, Zhang Y, Sigurgeirsson B, et al. Frequency of specic cancer types in dermatomyositis and polymyositis: a population-based study. Lancet. 2001 Jan 13;357:96-100. 7. Fardet L, Dupuy A, Gain M, et al. Factors associated with underlying malignancy in a retrospective cohort of 121 patients with dermatomyositis. Medicine (Baltimore). 2009 Mar;88:91-7. 8. Rozelle A, Trieu S, Chung L. Malignancy in the setting of the anti-synthetase syndrome. J Clin Rheumatol. 2008 Oct;14:285-8. 9. Chinoy H, Fertig N, Oddis CV, et al. The diagnostic utility of myositis autoantibody testing for predicting the risk of cancerassociated myositis. Ann Rheum Dis. 2007 Oct;66:1345-9. 10. Hengstman GJ, Vree Egberts WT, Seelig HP, et al. Clinical characteristics of patients with myositis and autoantibodies to different fragments of the Mi-2 beta antigen. Ann Rheum Dis. 2006 Feb;65:242-5. 11. Madan V, Chinoy H, Grifths CE, et al. Dening cancer risk in dermatomyositis. Part II. Assessing diagnostic usefulness of myositis serology. Clin Exp Dermatol. 2009 Jul;34:561-5. 12. Selva-OCallaghan A, Grau JM, Gamez-Cenzano C, et al. Conventional cancer screening versus PET/CT in dermatomyositis/polymyositis. Am J Med. 2010 Jun;123:558-62. 13. Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum. 2007 Dec 15;57:1473-80. 14. Kermani TA, Schafer VS, Crowson CS, et al. Cancer preceding giant cell arteritis: a case-control study. Arthritis Rheum.

Conclusion
The delineation of an underlying malignancy from a primary rheumatic disease can be a challenge for the astute clinician. There is currently no consensus on which patients or how extensively to screen for malignancy in rheumatic syndromes. It is neither practical nor cost effective to perform an extensive search for malignancy in most patients with rheumatic conditions, unless they have features suggesting an occult neoplasia including: Personal or family history of malignancy, Exposure to carcinogens or medications known to cause malignancy, Severe or atypical presentation, Asymmetric or explosive onset arthritis in the elderly, Constitutional features out of proportion with the degree of arthritis, Paraneoplastic syndrome, Failure to respond to traditional therapies, or Presence of serologic markers of malignancy (tumor markers and autoantibodies).

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Bulletin of the NYU Hospital for Joint Diseases 2012;70(2):109-14 31. Hoff AO, Gagel RF. Osteoporosis in breast and prostate cancer survivors. Oncology (Williston Park). 2005 Apr;19:651-8. 32. Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003 Nov 1;21:4042-57. 33. Daniell HW. Osteoporosis after orchiectomy for prostate cancer. J Urol. 1997 Feb;157:439-44. 34. Bannwarth B. Drug-induced rheumatic disorders. Rev Rhum Engl Ed. 1996 Nov;63:639-47. 35. Tinazzi E, Ficarra V, Simeoni S, et al. Reactive arthritis following BCG immunotherapy for urinary bladder carcinoma: a systematic review. Rheumatol Int. 2006 Apr;26:481-8. 36. Aljada IS, Crane JK, Corriere N, et al. Mycobacterium bovis BCG causing vertebral osteomyelitis (Potts disease) following intravesical BCG therapy. J Clin Microbiol. 1999 Jun;37:2106-8. 37. Vogelzang NJ, Bosl GJ, Johnson K, et al. Raynauds phenomenon: a common toxicity after combination chemotherapy for testicular cancer. Ann Intern Med. 1981 Sep;95:288-92. 38. Hansen SW, Olsen N. Raynauds phenomenon in patients treated with cisplatin, vinblastine, and bleomycin for germ cell cancer: measurement of vasoconstrictor response to cold. J Clin Oncol. 1989 Jul;7:940-2. 39. Kerr LD, Spiera H. Scleroderma in association with the use of bleomycin: a report of 3 cases. J Rheumatol. 1992 Feb;19:2946. 40. Adelman H, Carter JD, Ricca L, Sterrett A. Case 26. In: Valeriano J, Bateman H, (eds): Visual Diagnosis Self-tests on Rheumatology (3rd ed). Boca Raton, FL: Merit Publishing, 2009, pp. 125-126. 41. Tsukadaira A, Okubo Y, Takashi S, et al. Repeated arthralgia associated with granulocyte colony stimulating factor administration. Ann Rheum Dis. 2002 Sep;61:849-50. 42. Ioannou Y, Isenberg DA. Current evidence for the induction of autoimmune rheumatic manifestations by cytokine therapy. Arthritis Rheum. 2000 Jul;43:1431-42. 43. Nissen MJ, Fontanges E, Allam Y, et al. Rheumatological manifestations of hepatitis C: incidence in a rheumatology and non-rheumatology setting and the effect of methotrexate and interferon. Rheumatology (Oxford). 2005 Aug;44:1016-20. 44. Esteva-Lorenzo FJ, Janik JE, Fenton RG, et al. Myositis associated with interleukin-2 therapy in a patient with metastatic renal cell carcinoma. Cancer. 1995 Oct 1;76:1219-23. 45. Stevens AM, Sullivan KM, Nelson JL. Polymyositis as a manifestation of chronic graft-versus-host disease. Rheumatology (Oxford). 2003 Jan;42:34-9.

2010 Jun;62:1763-9. 15. Myklebust G, Wilsgaard T, Jacobsen BK, et al. No increased frequency of malignant neoplasms in polymyalgia rheumatica and temporal arteritis. A prospective longitudinal study of 398 cases and matched population controls. J Rheumatol. 2002 Oct;29:2143-7. 16. Liozon E, Loustaud V, Fauchais AL, et al. Concurrent temporal (giant cell) arteritis and malignancy: report of 20 patients with review of the literature. J Rheumatol. 2006 Aug;33:1606-14. 17. Naschitz JE, Slobodin G, Yeshurun D, et al. Atypical polymyalgia rheumatica as a presentation of metastatic cancer. Arch Intern Med. 1997 Nov 10;157:2381. 18. Buggiani G, Krysenka A, Grazzini M, et al. Paraneoplastic vasculitis and paraneoplastic vascular syndromes. Dermatol Ther. 2010 Nov;23:597-605. 19. Tincani A, Taraborelli M, Cattaneo R. Antiphospholipid antibodies and malignancies. Autoimmun Rev. 2010 Feb;9:200-2. 20. Miesbach W, Asherson RA, Cervera R, et al. The role of malignancies in patients with catastrophic anti-phospholipid (Ashersons) syndrome. Clin Rheumatol. 2007 Dec;26:210914. 21. Kim MJ, Ye YM, Park HS, et al. Chemotherapy-related arthropathy. J Rheumatol. 2006 Jul;33:1364-8. 22. Warner E, Keshavjee al N, Shupak R, et al. Rheumatic symptoms following adjuvant therapy for breast cancer. Am J Clin Oncol. 1997 Jun;20:322-6. 23. Amft N, DCruz D. Postchemotherapy connective tissue diseases--more than just rheumatism? Lupus. 1996 Aug;5:255-6. 24. Raderer M, Scheithauer W. Postchemotherapy rheumatism following adjuvant therapy for ovarian cancer. Scand J Rheumatol. 1994;23:291-2. 25. Loprinzi CL, Duffy J, Ingle JN. Postchemotherapy rheumatism. J Clin Oncol. 1993 Apr;11:768-70. 26. Crew KD, Greenlee H, Capodice J, et al. Prevalence of joint symptoms in postmenopausal women taking aromatase inhibitors for early-stage breast cancer. J Clin Oncol. 2007 Sep 1;25:3877-83. 27. Donnellan PP, Douglas SL, Cameron DA, et al. Aromatase inhibitors and arthralgia. J Clin Oncol. 2001 May 15;19:2767. 28. Moxley G. Rheumatic disorders and functional disability with aromatase inhibitor therapy. Clin Breast Cancer. 2010 Apr;10:144-7. 29. Felson DT, Cummings SR. Aromatase inhibitors and the syndrome of arthralgias with estrogen deprivation. Arthritis Rheum. 2005 Sep;52:2594-8. 30. Lester J, Coleman R. Bone loss and the aromatase inhibitors. Br J Cancer. 2005 Aug;93 Suppl 1:S16-22.