Malignancy and rheumatic disorders

INTRODUCTION — There are complex bidirectional relationships between rheumatic diseases and cancer. Certain rheumatic disorders, including dermatomyositis, polymyositis, rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren's syndrome, and systemic sclerosis, are associated with an increased risk of malignancy and in some instances may be the result of cancer-induced autoimmunity [1-3]. In addition, treatments for rheumatic diseases may also increase malignancy risk.

Conversely, some malignancies may present or be associated with joint, muscle, and soft tissue manifestations [1,4]. The malignancies with the most frequent musculoskeletal findings are leukemias and lymphomas, but paraneoplastic syndromes also occur with solid tumors. Additionally, therapies for malignancy sometimes cause rheumatic disease syndromes.

Specific rheumatic diseases and risk of malignancies, the contribution of antirheumatic drug therapies to such risk, paraneoplastic rheumatic disorders and rheumatic presentations of malignant disorders, and rheumatic symptoms or disorders caused by anti-tumor therapies will be reviewed here. The relationship of inflammatory myositis to malignancy is discussed in detail separately. (See "Malignancy in dermatomyositis and polymyositis".)

RHEUMATIC DISEASES WITH ASSOCIATED MALIGNANT DISORDERS — A number of the major rheumatic disorders are associated with an increased risk for various malignancies (table 1) [5]. The reasons for this risk are not well defined, but they are likely to involve both chronic inflammation triggering malignancy and autoimmunity arising as a byproduct of naturally occurring anti-tumor immune responses (table 2) [5]. Indeed, further data suggest that immune-mediated diseases may be associated with an increased risk of cancer in organs that are involved by the disease process [6].

Rheumatic diseases in this group include dermatomyositis, polymyositis, rheumatoid arthritis (RA), systemic lupus erythematosus, Sjögren's disease, and systemic sclerosis [1,2]. (See 'Risk of malignancy in rheumatic disease' below.)

Patients with rheumatic disease should receive age- and sex-appropriate screening for malignancy, as well as screening appropriate to individual risk factors that may be present. (See 'Screening for malignancy in rheumatic disease' below and "Overview of preventive care in adults", section on 'Cancer screening'.)

Risk of malignancy in rheumatic disease

Dermatomyositis and polymyositis — Cancer is of greatest concern in patients with dermatomyositis and, to a lesser degree, polymyositis. A wide array of cancer types may be seen in these diseases, and, in dermatomyositis, the risk of cancer is increased in the first five years of disease. The strength of this association and recommendations for initial screening for malignant disease in patients with newly diagnosed inflammatory myopathy are presented separately. (See "Malignancy in dermatomyositis and polymyositis".)

Rheumatoid arthritis — The risk of lymphoma is increased moderately by the presence of RA, as is the risk of lung cancer [7]. A meta-analysis of 12 observational studies indicated that patients with a history of RA and cancer who started treatment with a biologic disease-modifying antirheumatic drug (DMARD; including tumor necrosis factor [TNF] inhibitors, abatacept, rituximab, and tocilizumab) did not have an increased risk of new or recurrent malignancy (rate ratio [RR] 1.09) [8]. Other drugs used to treat RA, including alkylating agents, azathioprine, methotrexate, and Janus kinase (JAK) inhibitors, may contribute to the risk, although not all patients with RA who develop malignancies have been treated with any of these drugs. The etiology of neoplasia in such patients may include immune dysregulation and/or chronic immune activation. The risk of lymphoproliferative diseases in RA is discussed in more detail elsewhere. (See "Disease outcome and functional capacity in rheumatoid arthritis", section on 'Lymphoproliferative disorders'.)

Systemic lupus erythematosus — There is a substantially increased risk of lymphoid malignancy, primarily non-Hodgkin lymphoma, among patients with systemic lupus erythematosus. Whether or not there is a higher risk of other malignancies is less certain. Virus-associated malignancies may be increased in systemic lupus erythematosus, whereas the risk of breast and prostate cancers is less than in the general population. These associations are discussed in more detail elsewhere. (See "Overview of the management and prognosis of systemic lupus erythematosus in adults", section on 'Prognosis'.)

Sjögren's disease — Sjögren's disease has an established association with the development of lymphoproliferative malignancy. The spectrum of malignant lymphoproliferation extends from an increased frequency of circulating monoclonal immunoglobulins, free light chains, and mixed cryoglobulins (type II mixed cryoglobulinemia) to non-Hodgkin lymphoma of the mucosa-associated lymphoid tissue (MALT) type. (See "Clinical manifestations of Sjögren’s disease: Extraglandular disease", section on 'Hematologic manifestations'.)

Systemic sclerosis (scleroderma) — Systemic sclerosis (SSc; scleroderma) is associated with an increased risk of lung, liver, hematologic, bladder, and tongue cancers, but many other malignancies can also be seen. As in dermatomyositis, subsets of SSc patients, identified by distinct autoantibodies, may have an increased risk of cancer at the time SSc develops. While there is not an increased risk of breast cancer overall in SSc, breast cancer is commonly diagnosed concurrent with SSc developing [9]. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults", section on 'Other disease associations'.)

Systemic vasculitis — Systemic necrotizing vasculitis has been seen in association with hairy cell leukemia. Polyarteritis nodosa has been associated with solid tumors, lymphoid malignancies, and myelodysplasia [10,11]. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis carries a 1.6 to 2.0 higher risk for developing malignancy than the general population [12]. Various cancer types have been observed, particularly urinary tract cancer and leukemia, which may reflect use of cyclophosphamide in these patients [12]. (See "Clinical features and diagnosis of hairy cell leukemia".)

Polymyalgia rheumatica/giant cell (temporal) arteritis — The association between malignancy and polymyalgia rheumatica or giant cell arteritis is uncertain, given the lack of strong supportive evidence. A meta-analysis of patients with polymyalgia rheumatica or giant cell arteritis found a slightly increased risk of malignancy (risk ratio 1.14, 95% CI 1.05-1.22) that was highest in the 6 to 12 months following the diagnosis of polymyalgia rheumatica or giant cell arteritis, but these findings were not statistically significant when a study with possible selection bias was excluded from the analysis [13]. Symptoms that mimic polymyalgia rheumatica may be the presenting manifestation of a malignancy [1,14,15]. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica" and "Clinical manifestations of giant cell arteritis".)

Screening for malignancy in rheumatic disease — In autoimmune diseases with known increased cancer risk at disease onset, like SSc or myositis, there is a question of how to appropriately screen patients for an underlying cancer. Ensuring that age- and sex-appropriate cancer screening has been performed is an important first step (see "Overview of preventive care in adults", section on 'Cancer screening'). Beyond this, cancer screening should be targeted to risk factors that are unique to each patient.

For certain disorders, awareness of the particular autoantibodies that are associated with the most risk can help stratify patients. As an example, in myositis, patients with antibodies to nuclear matrix protein-2 (NXP2) and transcriptional intermediary factor 1 (TIF1) gamma are more likely to have cancer within three years of disease onset than patients in other autoantibody groups [16]. Similarly, in SSc, patients with anti-RNA polymerase III or anti-RNPC3 (also known as U11/U12) antibodies are more likely to have cancer-associated SSc [17-19]. Additional findings suggest that autoantibody type and cutaneous subtype (diffuse versus limited) in SSc may also define cancer risk, type, and timing in scleroderma [20]. For instance, compared with the general population, patients with RNA polymerase III antibodies and diffuse SSc have an increased risk of breast cancer, prostate cancer, and tongue cancer within three years of SSc onset, while those with RNA polymerase III antibodies and limited SSc have a high lung cancer risk at disease onset.

PARANEOPLASTIC RHEUMATIC MANIFESTATIONS — A variety of musculoskeletal and vascular immune-mediated conditions may occur that are frequently associated with the presence of an underlying malignancy. In some patients, these disorders remit with treatment of the malignancy, and they can thus be described as paraneoplastic rheumatic manifestations in those patients in whom such a malignancy is detected. Patients with potentially paraneoplastic rheumatic syndromes, such as palmar fasciitis, leukocytoclastic vasculitis, hypertropic osteoarthropathy, and remitting symmetrical seronegative synovitis with pitting edema (RS3PE), should be evaluated for underlying malignancy as part of their care. The evaluation and testing performed depend upon the particular rheumatic syndrome and the individual patient's risk factors.

Remitting seronegative symmetrical synovitis with pitting edema — Usually occurring in older adults, RS3PE presents with edema of the hands and feet along with synovitis (picture 1). Concurrent malignancy is common with this condition; its prevalence among patients with RS3PE has been found to be from 16 to 30 percent [21,22]. The array of malignancies associated with RS3PE is broad, from hematologic (leukemia, myelodysplastic syndrome, and lymphoma) to solid tumors (prostate, breast, gastrointestinal, lung, ovarian, bladder, and endometrial) [22]. Initial evaluation of a patient with RS3PE should involve updating age-appropriate cancer screening and taking a careful history for any symptoms that suggest an underlying malignancy. (See "Clinical manifestations and diagnosis of polymyalgia rheumatica", section on 'Differential diagnosis'.)

Cutaneous small vessel vasculitis — Small vessel vasculitis, often limited to the skin, causing palpable purpura or ulceration and having histologic features of fragmented leukocytes (leukocytoclastic), has been noted in the setting of a variety of malignant diseases [10,11]. Hematologic malignancies were approximately twice as common as solid tumors in one series of patients with malignancy-associated vasculitis [10], but a diverse group of both types of tumors has been reported. Given that there is no preponderance of a particular type of cancer, initial evaluation should focus on a thorough history and physical examination and age- and sex-appropriate cancer screening. (See "Cutaneous manifestations of internal malignancy", section on 'Vasculitis'.)

Paraneoplastic polyarthritis — Paraneoplastic inflammatory arthritis has been described with a variety of tumor types. Symmetric polyarthritis affecting the wrists and small joints of the hands, mimicking rheumatoid arthritis (RA), can occur as a paraneoplastic phenomenon, but such arthritis is relatively rare [23]. In one series of 65 patients, the features distinguishing paraneoplastic presentations from RA were a male predominance, asymmetric onset, and high markers of inflammation [24]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

Patients with myelodysplastic syndromes sometimes also develop polyarthritis that may be confused with seronegative RA. As an example, a cohort study of 87 patients with myelodysplastic syndromes reported five with inflammatory arthritis resembling RA [25]. We refer patients with clinical features suggestive of a paraneoplastic polyarthritis for further evaluation by an expert in hematology/oncology or another appropriate specialty, depending upon on our clinical evaluation and the findings on a complete blood count with differential (eg, unexplained anemia or abnormal white blood cell differential). (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Autoimmune/inflammatory conditions'.)

Palmar fasciitis and polyarthritis syndrome — Palmar fasciitis (sometimes referred to as palmar fibromatosis) is a rare disorder associated with a variety of malignant neoplasms. The most frequently reported tumor is ovarian cancer, but other primary sites, including the stomach, pancreas, lung, colon, and prostate, have also been described in association with this disorder [26-28]. Polyarthritis may accompany the fibrosis.

The fibrosis or fibromatosis of the palms leads to progressive flexion deformities of the fingers, usually affecting all the digits of both hands (picture 2). The changes in the palmar skin and fascia and the resulting flexion deformities are reminiscent of Dupuytren contracture but are more widespread than in that disease, and progressive changes lead to an appearance and texture of "woody hands" [27,29]. Treatment of an associated malignancy has led to improvement in some cases and has halted progression in others [30]. Glucocorticoids and disease-modifying antirheumatic drugs (DMARDs) have had minimal effect, as documented in a systematic review [30]. Malignant disease has not been identified in all cases. Physical therapy and occupational therapy may also help improve function [31].

Patients who present with symptoms of palmar fibromatosis and do not have a known malignancy should undergo screening for cancer. Age-appropriate cancer screening should be performed and, for women, given the association with ovarian cancer [30], pelvic ultrasound may also be helpful. In patients with a high index of suspicion clinically for cancer, other testing such as further imaging or checking tumor markers may be performed.

Eosinophilic fasciitis — Eosinophilic fasciitis (EF) is an uncommon condition, typically characterized by woody induration, which most often affects the limbs (forearms and calves), trunk, or neck with sparing of the hands and face. The skin may be edematous early in the disease course and exhibit dimpling with a peau d'orange appearance (picture 3) [32]. In later stages, induration of subcutaneous tissues can develop, resulting in a woody or marble-like feel, and venous grooving may be observed (picture 4) [32]. There is often peripheral eosinophilia.

It is most often idiopathic but can be associated in up to 10 percent of patients with any of a variety of hematologic disorders [33,34]. The associated disorders include immune-mediated anemia or thrombocytopenia, pancytopenia, aplastic anemia, pure red cell aplasia, Hodgkin lymphoma, myelomonocytic leukemia, chronic lymphocytic leukemia, other leukemias and lymphomas, multiple myeloma, and other myeloproliferative disorders [32,33]. The features and management of EF are discussed in detail separately. (See "Eosinophilic fasciitis".)

Given the association with hematologic disorders, obtaining a complete blood count with differential and asking the patient about any B symptoms such as fevers, night sweats, or weight loss should be a part of an initial evaluation.

Erythromelalgia — Erythromelalgia is a rare syndrome characterized by attacks of warmth, pain, and redness involving the extremities (picture 5A-B). It can be associated with myeloproliferative disorders, particularly polycythemia vera and essential thrombocythemia, but this association appears to be present in less than 10 percent of patients [35,36]. (See "Erythromelalgia".)

Hypertrophic osteoarthropathy — Hypertrophic osteoarthropathy, which can be associated with lung cancer, other pulmonary disorders, and several other conditions, is a syndrome characterized by abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities. Clinical features include digital clubbing (figure 1), periostosis of tubular bones (image 1A-B), and synovial effusions, which are most prominent in the large joints. Periostosis is usually accompanied by pain on palpation of the involved area. Some patients present with a painful arthropathy in advance of clubbing and may be thought initially to have an inflammatory arthritis [37].

The secondary form of hypertrophic osteoarthropathy, discussed here, is usually associated with lung cancer, pulmonary infections, cystic fibrosis, and right-to-left cardiac shunts and can be seen less often in other conditions (eg, Hodgkin lymphoma and cirrhosis). A separate disorder, termed primary (or idiopathic) hypertrophic osteoarthropathy or pachydermoperiostosis, is a hereditary disorder that presents in childhood and mimics secondary form [38-40]. Clubbing and hypertrophic osteoarthropathy appear to be different manifestations of the same disease process [41,42]. However, the pathogenesis of (secondary) hypertrophic osteoarthropathy remains poorly defined. Hypotheses have been proposed involving different mechanisms, with suggested roles for platelet derived and other growth factors; circulatory bypass of the lung by megakaryocytes that could release growth factors in the distal extremities [41,43]; tumor-derived production and release of a factor, such as vascular endothelial growth factor (VEGF), that might promote features of the condition such as vascular proliferation, edema formation, and new bone formation [44,45]; and a role, as described in primary hypertrophic osteoarthropathy, for elevated levels of circulating prostaglandin E2.

Among patients with lung cancer, the condition is most frequently associated with adenocarcinoma and least frequently with small cell carcinoma. In one series of 111 consecutive patients with pathologically proven lung cancer, clubbing was present in 29 percent; clubbing was more common among women than men (40 versus 19 percent) and in non-small cell compared with small cell lung cancer (35 versus 4 percent) [46]. In a study of 2625 Japanese patients with lung cancer, hypertrophic osteoarthropathy was detected by bone scintigraphy in 19 patients (0.7 percent) [47].

When the diagnosis is suspected, particular attention should be paid to the chest because the most frequent cause of acute onset of hypertrophic osteoarthropathy is a lung neoplasm, either primary or secondary. Bone scintigraphy is a sensitive way to detect skeletal involvement with the disorder.

Treatment with nonsteroidal antiinflammatories or other analgesics may provide significant symptomatic relief. Removal of lung cancer or treatment of the other causes results in regression in the clinical manifestations in many patients but is not always effective [47,48]. In patients with refractory disease, bisphosphonates, including pamidronate and zoledronic acid, have been reported to be highly effective in a number of case reports [48-53].

MALIGNANT DISEASES WITH MUSCULOSKELETAL MANIFESTATIONS — A variety of malignancies can have musculoskeletal manifestations [1,54-56]. Perhaps most common is bone pain with bone metastases and in patients with multiple myeloma, which are discussed separately. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults" and "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Bone pain'.)

In addition to the various paraneoplastic rheumatologic syndromes (see 'Paraneoplastic rheumatic manifestations' above), articular and systemic autoimmune phenomena can also occur as a more direct consequence of some malignancies, especially lymphoproliferative and myelodysplastic disorders. (See 'Lymphoma' below and 'Large granular lymphocyte syndrome' below and 'Leukemia' below and 'Myelodysplasia' below.)

In some cases, the rheumatic symptoms are the presenting feature of the disease. In one series of patients admitted to a general hospital ward with a previously unclarified rheumatic disease, 23 percent had an occult malignancy [56]. Remission of the tumor was often associated with improvement in rheumatic symptoms.

Lymphoma — Articular symptoms in patients with lymphoma may result from secondary gout, as a reaction to adjacent lymphomatous involvement, or due to lymphomatous infiltration of the synovium [57]. Joint involvement is unusual in lymphoma and is primarily seen with T cell types [58]. Synovial fluid may show atypical lymphocytes, and synovial biopsies may demonstrate infiltration by lymphoma cells [59]. In rare cases, arthritis is a presenting feature of the disease [60].

Lymphomas may also have clinical features that can cause diagnostic confusion with systemic inflammatory and autoimmune rheumatic disorders, including those characterized by vascular and granulomatous inflammation. As examples:

●Patients with angioimmunoblastic T cell lymphoma may have arthritis, Coombs-positive hemolytic anemia, skin rash, fever, and weight loss that are suggestive of systemic lupus erythematosus or systemic-onset rheumatoid arthritis (RA [Still's disease]). Lymphohistiocytic vasculitis has been described as well. This type of T cell lymphoma is discussed in detail elsewhere. (See "Clinical manifestations, pathologic features, and diagnosis of angioimmunoblastic T cell lymphoma".)

●Angiocentric and angioinvasive lesions of various organs may be due to large B cell lymphomas. When there is predominantly (or exclusively) extranodal disease, T-cell-rich tissue infiltrates, extensive necrosis, and inflammation, this disorder may be confused with granulomatosis with polyangiitis. This type of disease, usually with prominent pulmonary involvement, is referred to as lymphomatoid granulomatosis, and it is discussed in more detail elsewhere. (See "Pulmonary lymphomatoid granulomatosis" and "Epidemiology, clinical manifestations, pathologic features, and diagnosis of diffuse large B cell lymphoma", section on 'Lymphomatoid granulomatosis'.)

Up to 15 percent of patients with Hodgkin lymphoma have radiographic evidence of bone involvement. Bone pain, which may be worse at night, is the most common symptom attributable to osseous involvement. Pathologic fractures, particularly involving the vertebrae, may occur. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

Lymphoma involving the muscles is uncommon. In one report, for example, 472 cases of lymphomas arising from the soft tissues were reported from a review of more than 39,000 consecutive cases over a 10-year period [61].

Large granular lymphocyte syndrome — Chronic lymphoproliferative disease related to clonal or nonclonal ("reactive") expansion of large granular lymphocytes (LGL) is characterized by mild to moderate lymphocytosis, bone marrow infiltration, splenomegaly, granulocytopenia (neutropenia), and anemia. Up to one-third of patients with the LGL syndrome also have RA [62] and may fulfill the clinical criteria for Felty syndrome (see "Large granular lymphocyte leukemia in rheumatoid arthritis" and "Treatment of large granular lymphocyte leukemia"). The clonal expansion of lymphocytes may also be related to the development of eosinophilic fasciitis (EF) [63].

Leukemia — Leukemia can present with symmetric or migratory polyarthritis/arthralgia as well as bone pain and tenderness [1,64-66]. The frequency of articular manifestations in acute leukemia is approximately 4 percent in adults and 14 percent in children [64]. The predominant leukemia causing arthritis in children is acute lymphocytic leukemia, and polyarthritis can be the presenting complaint. By comparison, acute and chronic lymphocytic and myeloid leukemia can cause arthritis in adults. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children".)

The pain in leukemic arthritis is usually severe and unresponsive to antirheumatic medication [60]. Radiographs often reveal more osteopenia and earlier lytic lesions than one would expect in a child with juvenile idiopathic arthritis.

Synovial infiltration by leukemic cells, hemorrhage into the joint and bone, and periosteal or capsular lesions can all account for the joint manifestations. Synovial biopsy can be diagnostic but may be negative because of the patchy nature of neoplastic involvement [67]. Immunocytologic analysis of the synovial fluid can also be helpful [68]. Leukemic synovitis is a sign of systemic involvement and should prompt immediate and aggressive therapy even in the absence of signs of bone marrow involvement [69].

Myelodysplasia — A variety of phenomena of suspected autoimmune pathogenesis has been reported in association with myelodysplastic syndromes. Among the rheumatic manifestations are inflammatory polyarthritis (rheumatoid or undifferentiated polyarthritis), monoarticular arthritis, polymyalgia rheumatica, remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome, relapsing polychondritis, Raynaud phenomenon, Sjögren's disease, and vasculitis. These and other disorders that may be associated with myelodysplasia are discussed in more detail elsewhere. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Autoimmune/inflammatory conditions' and "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Paraneoplastic and cancer treatment-related disease'.)

ANTIRHEUMATIC MEDICATIONS AND RISK OF MALIGNANCY — Pharmacologic therapy of rheumatic diseases may increase the risk of malignant disease. Alkylating agents, particularly cyclophosphamide, and other immunosuppressive and antiinflammatory drugs (eg, azathioprine, mycophenolate, and methotrexate), as well as certain antirheumatic biologic agents, may also increase the risk of hematologic and other malignancies. Discussion of the oncogenic potential of these medications is presented separately. (See "General toxicity of cyclophosphamide in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major side effects of low-dose methotrexate" and "Mycophenolate: Overview of use and adverse effects in the treatment of rheumatic diseases", section on 'Neoplasia' and "Tumor necrosis factor-alpha inhibitors: Risk of malignancy" and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Malignancy'.)

RHEUMATIC DISORDERS ASSOCIATED WITH TREATMENTS FOR MALIGNANT DISEASE — Various musculoskeletal or other connective tissue disorders may arise as the result of treatment of malignant disease. Among those are gouty arthritis resulting from hyperuricemia that accompanies a tumor burden, especially in lymphoproliferative disorders. Arthralgia or arthritis may follow or, less often, occur during adjuvant chemotherapy. These phenomena are referred to as postchemotherapy rheumatism or chemotherapy-related arthropathy, respectively [70,71]. (See 'Chemotherapy-related musculoskeletal conditions' below.)

Some other rheumatic or connective tissue disorders are associated with the use of particular chemotherapeutic agents and radiation therapy. Concerns have also been raised regarding whether the presence of a rheumatic disorder may potentially influence the risk of radiation therapy for the treatment of malignancy, but the degree of risk remains uncertain. (See 'Radiation therapy-related musculoskeletal conditions' below and 'Safety of radiation therapy for malignancy in patients with rheumatologic disease' below.)

Additionally, cancer immunotherapies, most notably immune checkpoint inhibitors, have been linked to a variety of rheumatic and musculoskeletal manifestations. (See 'Immune checkpoint inhibitor associated rheumatic conditions' below.)

Chemotherapy-related musculoskeletal conditions

Aromatase inhibitors — Aromatase inhibitors (table 3) used in the treatment of breast cancer are associated with an increased incidence of musculoskeletal complaints. Arthralgia and subjective joint stiffness are common complaints, occurring in 40 to 50 percent of women who are being treated with one of these agents. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Musculoskeletal pains and stiffness'.)

Bleomycin — Cases of systemic sclerosis (SSc; scleroderma) and Raynaud phenomenon have been noted in association with the use of bleomycin. (See "Risk factors for and possible causes of systemic sclerosis (scleroderma)", section on 'Drugs'.)

Taxanes — Taxanes, such as paclitaxel and docetaxel, can cause myalgia and arthralgia that is sometimes severe. Taxanes may also cause photodistributed skin rashes with clinical and histologic similarity to subacute cutaneous lupus and SSc-like disease. (See "Cutaneous adverse effects of conventional chemotherapy agents", section on 'Photosensitivity reactions'.)

Gemcitabine — SSc-like disease and critical digital ischemia have been reported in association with gemcitabine [72-74].

Glucocorticoids — Use of high-dose glucocorticoids is associated with an increased risk of developing osteonecrosis and osteoporosis, with the latter being associated with increased fracture risk. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

Bisphosphonates — Musculoskeletal pain, occasionally severe, rarely occurs with the use of these agents. Use of bisphosphonates has been associated with osteonecrosis of the jaw. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw'.)

Radiation therapy-related musculoskeletal conditions — Myalgia, stiffness, and elevation of serum creatine kinase following external neck irradiation may be the result of radiation-induced hypothyroidism. These symptoms may follow radiation therapy by months or even years. (See "Disorders that cause hypothyroidism", section on 'External neck irradiation' and "Hypothyroid myopathy".)

The most common long-term complication of radiation therapy and chemoradiotherapy for head and neck cancer is xerostomia, which is the result of damage to the salivary glands, and which may mimic the dry mouth of Sjögren's disease. External beam irradiation may also increase the risk of osteonecrosis. (See "Management of late complications of head and neck cancer and its treatment", section on 'Salivary gland damage and xerostomia' and "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis'.)

Similarly, radiation may trigger the development of morphea (localized scleroderma). Whether radiation can trigger de novo systemic sclerosis remains unknown. (See "Pathogenesis, clinical manifestations, and diagnosis of morphea (localized scleroderma) in adults".)

Safety of radiation therapy for malignancy in patients with rheumatologic disease — Some studies, including case series, have suggested that patients with systemic rheumatic diseases, especially those with systemic sclerosis (SSc; scleroderma) and possibly those with systemic lupus erythematosus, are at greater risk compared with patients without these disorders for toxic effects from radiotherapy used to treat malignant conditions [75-78]. Patients with rheumatoid arthritis (RA) do not appear at greater risk.

However, the small size of studies in the literature and variability in the results between studies prevents firm conclusions, and where an association has been suggested, the increased risk appears small compared with patients without these disorders. Based upon the data available, even SSc, for which the evidence is strongest, does not appear to be a contraindication to radiotherapy in all patients, and treatment decisions should be made on a case-by-case basis with careful consideration of the overall balance of the potential risks and benefits of therapy in the individual patient.

A 2006 systematic review found methodologic shortcomings in most studies and failed to demonstrate convincingly that patients with connective tissue disorders are at increased risk for late radiation-related toxic effects [79]. The risks associated with each specific connective tissue disorder were not analyzed. Similar conclusions were reached in a subsequent retrospective study of 20 SSc patients [80]; the short- and long-term rate of severe toxicity was not significantly higher compared with other patient cohorts receiving radiotherapy, and there were no severe acute skin reactions. There were no cases in which radiotherapy was believed to have exacerbated SSc, and the preponderance of deaths was related to the underlying malignancy rather than to SSc. In a subsequent multicenter, retrospective study of 153 SSc patients with breast cancer, 69 patients were treated with radiation therapy [81]. Up to 50 percent of the patients developed localized cutaneous fibrosis in the radiation port. However, generalized flares of SSc skin or lung disease were not observed, suggesting that radiation therapy for breast cancer could be considered a treatment option for SSc patients in the context of a multidisciplinary discussion and shared decision-making to explore the informed patient's preferences.

Immune checkpoint inhibitor associated rheumatic conditions — Immune checkpoint inhibitors are a type of cancer immunotherapy that work by blocking negative regulation of T cells. Off-target effects of these drugs are known as immune-related adverse events and can potentially affect a wide range of organs and tissues; among these are rheumatic and musculoskeletal adverse events, which include inflammatory arthritis, sicca syndrome, myositis, vasculitis, psoriatic arthritis, and polymyalgia rheumatica [82-86]. (See "Rheumatologic complications of checkpoint inhibitor immunotherapy" and "Toxicities associated with immune checkpoint inhibitors".)

Treatment of these events typically involves glucocorticoids, other immunosuppressive agents such as methotrexate or tumor necrosis factor (TNF)-inhibitors, and may involve holding or discontinuing the immune checkpoint inhibitor.

SUMMARY AND RECOMMENDATIONS

●Risk of malignancy in rheumatic disease – Individual rheumatic diseases are associated with increased risk of certain malignancies. Dermatomyositis, polymyositis, and systemic sclerosis (SSc; scleroderma) are associated with multiple types of malignancies, and rheumatoid arthritis (RA), Sjögren's disease, and systemic lupus erythematosus with lymphoid malignancy (table 1). Patients with myositis and SSc who possess certain antibodies (eg, RNA polymerase III antibodies in SSc) are at higher risk for having a malignancy close to the onset of their autoimmune disease. (See 'Risk of malignancy in rheumatic disease' above.)

●Screening for malignancy in rheumatic disease – In patients who are at risk for cancer related to their autoimmune disease, age- and sex-appropriate screening should be performed, and additional screening may be added based upon the risk factors of an individual patient. (See 'Screening for malignancy in rheumatic disease' above.)

●Paraneoplastic rheumatic manifestations – A number of paraneoplastic syndromes, such as palmar fasciitis, leukocytoclastic vasculitis, hypertropic osteoarthropathy, and remitting symmetrical seronegative synovitis with pitting edema (RS3PE), can occur with different malignancies. Patients with potentially paraneoplastic rheumatic syndromes should be evaluated for underlying malignancy as part of their care. The evaluation depends upon the particular rheumatic syndrome and the individual patient's risk factors. (See 'Paraneoplastic rheumatic manifestations' above.)

●Hypertrophic osteoarthropathy – Treatment of secondary hypertrophic osteoarthropathy with nonsteroidal antiinflammatories or other analgesics may provide significant relief of symptoms. Removal of lung cancer or treatment of the other causes of hypertrophic osteoarthropathy results in regression in the clinical manifestations in many patients, but is not always effective. Bisphosphonates have shown benefit in patients with refractory disease. (See 'Hypertrophic osteoarthropathy' above.)

●Malignant diseases with musculoskeletal manifestations – Rheumatic manifestations can be seen in malignancies, including articular manifestations in lymphoma, bone pain in multiple myeloma, symmetric or migratory polyarthralgia or arthritis in leukemia, and a variety of phenomena suspected to be autoimmune in myelodysplastic syndromes. Up to one-third of patients with large granular lymphocytic leukemia (LGL) also have RA. (See 'Malignant diseases with musculoskeletal manifestations' above and 'Lymphoma' above and 'Leukemia' above and 'Myelodysplasia' above and 'Large granular lymphocyte syndrome' above.)

●Antirheumatic medications and risk of malignancy – Some pharmacologic therapies used for the treatment of rheumatic diseases may increase the risk of malignancy. (See 'Antirheumatic medications and risk of malignancy' above.)

●Rheumatic disorders associated with treatment of malignancy – Treatment of malignant disease may cause various musculoskeletal or other connective tissue disorders. This includes treatment-induced hyperuricemia leading to gouty arthritis and adverse effects of adjuvant chemotherapy or immune checkpoint inhibition like arthralgia and arthritis. (See 'Rheumatic disorders associated with treatments for malignant disease' above and 'Chemotherapy-related musculoskeletal conditions' above and 'Radiation therapy-related musculoskeletal conditions' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Yusuf Yazici, MD, who contributed to an earlier version of this topic review.