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Chapter 50 Hypertrophic Osteoarthropathy and Other Rheumatic Manifestations of Neoplasia

Manual of Rheumatology and Outpatient Orthopedic Disorders

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Chapter 50 Hypertrophic Osteoarthropathy and Other Rheumatic Manifestations of Neoplasia

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Alan T. Kaell

Rheumatic syndrome as a manifestation of neoplasia
	Primary bone and joint neoplasms
	Tenosynovial sarcomas
	Lymphoproliferative disorders
	Paraproteinemias
	POEMS syndrome
	Metastatic carcinomatous arthritis associated with solid neoplasms
	Hypertrophic osteoarthropathy
	Rheumatoid arthritis and carcinomatous polyarthritis
	Reflex sympathetic dystrophy
	Erythromelalgia
	Sweet's syndrome
	Palmar fasciitis and polyarthritis
	Osteomalacia
	Miscellaneous musculoskeletal problems in patients with neoplasia
Malignancies associated with an established rheumatic syndrome
	Polymyositis
	RA
	Sjgren's syndrome
	Systemic sclerosis
	Immunodeficiency states
	Systemic Lupus Erythematosus
	Mixed cryoglobulinemia
	Paget's disease
	Multicentric reticulohistiocytosis
	Chronic osteomyelitis
Malignancy as a complication of antirheumatic therapy
	Alkylating agents
	Immunosuppressive Agents
Chemotherapeutic agents that may induce rheumatic-like disorders are the following
	Busulfan
	Cisplatin
	Bleomycin
	Fluorouracil
	Anthracyclines
	Cytosine arabinoside
	Any Immunosuppressive Therapy
	Hormonal manipulation
	Luteinizing hormone-releasing hormone (LHRH)
	Antibacterial and antiviral agents
	Cephalosporins
	Ciprofloxacin
	Radiation therapy
	Growth factors and biologic response modifiers
	Bone marrow
	Anti-thymocyte globulin
	Intravesical therapy
General recommendations
	Hypertrophic osteoarthropathy
	Dermatomyositis or polymyositis
	Cytotoxic or immunosuppressive therapy
	Immunodeficiency states
	Hepatitis C

If a close temporal relationship exists between the discovery of a malignancy and the onset of a rheumatic syndrome, an association is often presumed . In many cases, the association may be coincidental. In other cases, the response of the rheumatic syndrome to successful management of the malignancy suggests an interrelationship of the two problems. Similarly, the recurrence of a rheumatic syndrome that heralds or follows the relapse of a malignancy is an even stronger indication of a pathogenetic linkage.

The pathogenesis of a rheumatic syndrome may be known in a patient with metastatic joint involvement or gout. For most other conditions, such as hypertrophic (pulmonary) osteoarthropathy, the pathogenesis remains speculative . Humoral, cellular, neural, and vascular mechanisms have been suggested.

The relationship between various rheumatic syndromes and malignant neoplasms takes any one of several forms:

1. Rheumatic syndrome as a manifestation of an established or occult malignancy.
2. Malignancy occurring in the setting of an established rheumatic syndrome.
3. Malignancy as a complication of antirheumatic therapy.
4. Rheumatic syndrome as a complication of antineoplastic therapy.

I. Rheumatic syndrome as a manifestation of neoplasia

1. Primary bone and joint neoplasms. Primary bone tumors such as chondrosarcoma, giant cell tumor, and osteogenic sarcoma may present as monarticular pain. They can either directly invade the joint capsule and synovium or induce a synovial reaction by involving juxtaarticular bone.
2. Tenosynovial sarcomas are rare and usually present as a painless soft- tissue mass near a joint of the lower extremity . Extension directly into the joint is uncommon. Three subtypes of sarcoma and their typical locations include synovial (lower limb, distal upper limb), clear cell (heel, toes, ankles), and epithelioid (hand, wrist, forearm). Radiographic findings are nonspecific, and diagnosis is by biopsy. These tumors are probably of mesenchymal and not synovial cell origin.
3. Lymphoproliferative disorders
   1. Leukemia. Leukemic cells may directly infiltrate articular tissues. Poly-arthritis occurs more often with hematologic malignancies than with solid neoplasms. In childhood, the metaphyseal portion of bones is occupied by red marrow. Acute lymphocytic leukemia can present as a migratory or symmetric polyarthritis by infiltrating the periosteum, joint capsule, or metaphysis. It may even mimic rheumatic fever or juvenile rheumatoid arthritis (JRA). The ankle or knee is usually involved. Characteristically, the joint pain is quite severe and disproportionate to any physical findings. The erythrocyte sedimentation rate may be normal. Articular manifestations may develop before the appearance of leukemic cells in the peripheral blood. An elevated serum lactate dehydrogenase or mild leukopenia may help distinguish children with malignant neoplasms who present with musculoskeletal complaints from those who ultimately have JRA. In some cases, immunocytologic analysis can identify leukemic cells in synovial fluid.
   2. Vasculitis seen in leukemia is usually limited to cutaneous involvement (except for hairy-cell leukemia). Recurrent leukemic infiltrations into muscles may mimic localized, tender swelling of polyarteritis. Hairy-cell leukemia has been associated with polyarteritis nodosa. Rheumatic manifestations can precede or follow the clinical onset of leukemic symptoms and diagnosis. Rarely, temporal arteritis and polyarthritis, including rheumatoid arthritis (RA) and adult Still's disease, occur. Pathogenesis involves either leukemic infiltration or immune-driven inflammation .
   3. Lymphoma. Monarticular or polyarticular symptoms may be related to lymphomatous involvement of juxtaarticular bone. Both Hodgkin's and non-Hodgkin's lymphoma may present with musculoskeletal symptoms. This is attributed to either induction of a synovial reaction by adjacent osseous lymphoma or direct invasion of the joint capsule or synovium. In patients with T-cell lymphomas, a chronic polyarthritis may also develop.

      Vasculitis associated with lymphoma is usually limited to cutaneous involvement, presumably on an immune basis. In rare patients with intravascular lymphoma, multiorgan involvement may mimic vasculitis and symmetric polyarthritis.

   4. Angioimmunoblastic lymphadenopathy can be associated with rash, polyarthritis, polyclonal hypergammaglobulinemia, and Coombs'-positive hemolytic anemia. This condition may mimic systemic lupus erythematosus (SLE).
   5. Myelodysplastic disorders have also been associated with a variety of musculoskeletal symptoms and signs, including polyarthritis, lupuslike conditions, polychondritis, vasculitis, and erythromelalgia.
   6. Gout, secondary to rapid cell turnover or tumor lysis, is seen mainly in leukemias and lymphomas. Institution of allopurinol helps prevent this complication. The dosage of azathioprine and 6-mercaptopurine must be reduced if the patient receives concomitant allopurinol therapy.
4. Paraproteinemias. Amyloid arthropathy attributed to deposition of AL protein is associated with dysproteinemias, such as multiple myeloma. It occurs in up to 5% of myeloma patients and is more common in men and those with l light chains. This arthropathy can mimic RA and is associated with carpal tunnel syndrome, shoulder pad sign, and nodules. Erosions are rarely noted. Additional clinical clues that warrant consideration of amyloidosis are hepatosplenomegaly, congestive heart failure, macroglossia, pinch purpura, raccoon eyes, and nephrosis. Biopsy sites to establish a tissue diagnosis include abdominal fat, rectum , synovium, and bone marrow. (see Chapter 51, section I .)
5. POEMS syndrome (plasma cell dyscrasia with p olyneuropathy, o rganomegaly, e ndocrinopathy, m onoclonal protein, and s kin changes) can mimic a systemic, multiorgan rheumatic disorder . The skin changes are similar to those of scleroderma.

   Raynaud's syndrome, digital ischemic necrosis, and vasculitis may occur in patients with dysproteinemias.

   Tendon xanthomas, typically seen in familial hypercholesterolemia, have been reported with near-normal lipid levels in patients with dysproteinemias such as multiple myeloma and monoclonal gammopathy of unknown significance (MGUS).

6. Metastatic carcinomatous arthritis associated with solid neoplasms. Metastatic deposits of solid neoplasms in bone, synovium, or periarticular tissue can masquerade as monarthritis or polyarthritis. This is a rare occurrence. The synovial membrane can either react nonspecifically to adjacent malignant deposits or, less commonly, contain tumor itself. In general, the incidence of appendicular bone metastases lessens with increasing distance from the axial skeleton. Phalangeal metastases are usually caused by bronchogenic or gastrointestinal carcinomas and can mimic gout, osteomyelitis, osteoarthritis , or even RA. Metastatic breast carcinoma is the most common cause of metastatic carcinomatous arthritis in women. Joint effusions can rarely be associated with solid tumors in the absence of radiographically apparent periarticular osseous metastasis. In such cases, synovial fluid cytology or synovial tissue biopsy specimens may be positive for tumor cells in two- thirds of patients. In patients with unresponsive or progressive unilateral sacroiliitis, additional imaging and biopsy should be considered to detect metastatic carcinoma.

   In children, neuroblastoma should be considered as a cause of metastatic carcinomatous arthritis. In most instances, the primary neoplasm is evident. If the tumor is occult, tomography , bone scan, or biopsy becomes necessary for accurate diagnosis. In general, therapy is directed toward the underlying neoplasm.

7. Hypertrophic osteoarthropathy
   1. The clinical presentation is one of periostitis and chronic periosteal reaction. Periostitis occurs predominantly at the distal ends of the long bones. The term periostosis may more accurately describe these radiologic changes without necessarily implying an inflammatory mechanism. If early periostitis is not evident on plain radiographs, bone scan is useful in demonstrating its presence. Patients present with symmetric painful tenderness and swelling near the wrist and ankle regions . The discomfort is typically exacerbated by dependency of the limb and relieved by elevation.

      Note: Periostitis without clubbing does not constitute hypertrophic osteoarthropathy. Periostitis alone can occur in hypervitaminosis A, thyroid acropathy, retinoic acid toxicity, hyperphosphatemia, sarcoidosis, and Caffey's disease.

   2. Clubbing of the fingers. Although finger clubbing is invariably present, it may develop only after pain in the distal long bones occurs. The characteristic bulbous deformity or drumstick appearance of the fingertips is easy to recognize. However, before obvious clubbing develops, the only abnormality may be a nail that can be rocked or floated upon its nail bed to produce a spongy sensation . Next, the ungual-phalangeal angle (the angle between the nail plate and the proximal digit) increases beyond 160 degrees and becomes obliterated at 180 degrees. Alternatively stated, the normal nail plate forms an angle of 20 degrees or more dorsally with the axis of the digit. The circumference of the nail bed becomes greater than the circumference of the distal interphalangeal joint. The nail may eventually appear convex, like a watch crystal. A very rare, familial form of hypertrophic osteoarthropathy is pachydermoperiostitis. This is not associated with any underlying disorder and is typically associated with coarse facial features and painless periostitis.

      In synovial hypertrophy, with or without joint effusions, synovitis affects predominantly the knees and ankles but may also involve metacarpophalangeal and proximal interphalangeal joints. Effusions, if present, are typically not inflammatory.

      Underlying disorders should always be considered in patients with hypertrophic osteoarthropathy (Table 50-1). Associated conditions include pleural, pulmonary, cardiovascular, gastrointestinal, hepatic, and miscellaneous diseases. Although clubbing occurs in the majority of patients with cyanotic congenital heart disease and cystic fibrosis, it is seen in fewer than 5% of patients with the other disorders listed. Neoplasms and chronic suppurative diseases predominate. Overall, pulmonary problems dominate in most series of patients with hypertrophic osteoarthropathy. Bronchogenic carcinoma and suppurative lung disease are the two most common associated pulmonary conditions. The incidence of hypertrophic osteoarthropathy in these diseases is 2% and 5%, respectively.

      
      

      Table 50-1. Conditions associated with hypertrophic osteoarthropathy

      
      
      
   3. Treatment. If a neoplasm can be successfully resected, the presenting musculoskeletal symptoms of hypertrophic osteoarthropathy often resolve within weeks. A patient with inoperable bronchogenic carcinoma may respond to chemotherapy or radiation therapy. In those patients with an untreatable underlying disorder, chemical or surgical vagotomy may be beneficial. NSAIDs can be helpful in the control of local joint symptoms.
8. Rheumatoid arthritis and carcinomatous polyarthritis
   1. Rheumatoid arthritis. Classic RA has never been clearly documented as a sign of occult malignancy. Some reports in which RA was purported to be an initial manifestation of malignancy likely included patients with hypertrophic osteoarthropathy. The detection of a solid neoplasm shortly after the onset of RA most probably represents a chance occurrence. Rheumatoid factors occur in the serum of up to 20% of patients with solid neoplasms. Seropositivity and RA-like nodules have on occasion been described in patients with leukemia, including hairy-cell leukemia.
   2. Carcinomatous polyarthritis. The concept of a rheumatoid-like arthropathy that heralds a malignancy remains controversial (Table 50-2). Typically, the diagnosis of a seemingly related malignancyusually prostate, breast, or lung canceris made about 3 to 10 months after the onset of arthropathy. This arthritis typically differs from RA in that it is sudden in onset and is typically an asymmetric polyarthritis of predominantly the lower extremities; the wrist and small joints are spared. Subcutaneous nodules and rheumatoid factor are absent. Distinctive radiographic and synovial fluid findings have not been reported. The arthropathy may respond to anticancer therapy. In general, an age-appropriate malignancy assessment is appropriate in patients presenting with new-onset arthritis.
      
      

      
      

      Table 50-2. Rheumatic syndromes and the cancers they may herald

      
      
      
   3. Dermatomyositis and polymyositis
      1. Clinical presentation. Overall, malignancy occurs in 5% to 20% of persons with myositis. Dermatomyositis has a stronger association with cancer than does polymyositis. The association is most apparent in men older than 40 years. Myositis may precede the discovery of a malignancy by several months to a few years . Among the many types of malignancies that present with myositis, lung, breast, and ovarian carcinoma are the most common. In the absence of an easily detectable neoplasm defined as part of an age-appropriate malignancy assessment, an exhaustive search for an occult malignancy may not be cost-effective . Patients with interstitial lung disease and antibodies to Jo-1 appear less likely to have an associated malignancy.
      2. Treatment. Corticosteroids, with or without cytotoxic agents, remain the mainstay of therapy. Severe, progressive myositis that responds poorly to steroid therapy may improve after successful treatment of the neoplasm.
   4. Subcutaneous fat necrosis, arthritis, and eosinophilia. Panniculitis, with or without monarthritis or polyarthritis, may herald pancreatic carcinoma. Painful nodules or periarticular fat necrosis often precedes the onset of abdominal pain. Eosinophilia is variably present. In a male patient with subcutaneous fat necrosis and monarthritis or polyarthritis, pancreatic carcinoma should be strongly suspected, especially when eosinophilia is present.

      Endocrine tumors can mimic a variety of rheumatic disorders. Pituitary tumors causing acromegaly mimic polyarthritis; carcinoid can mimic scleroderma; pheochromocytoma can mimic vasculitis.

   5. Vasculitis
      1. Palpable purpura. An unexplained necrotizing cutaneous vasculitis warrants consideration of, or surveillance for, an underlying lymphoreticular or myelodysplastic disorder. Vasculitis, including giant cell arteritis, is also rarely associated with solid neoplasms. The mechanism is likely immune-mediated and not attributable to direct vascular involvement by tumor, except in the rare case of intravascular lymphoma (see section I.C.3 ). Cutaneous vasculitis as a paraneoplastic syndrome is unusual. Only 8 of 192 patients (4.2%) with cutaneous vasculitis had an underlying malignancy. Six of the eight were hematologic malignancies.
      2. Raynaud's disease, digital ulcers, purpura, and gangrene. Serum cryoproteins associated with plasma cell dyscrasias and lymphomas should be considered. Cryofibrinogen, evident in plasma, is associated with metastatic malignancy. Anti-cardiolipin antibodies may also be associated with malignancy (see below).
      3. Polyarteritis nodosa may rarely develop in patients with hairy-cell leukemia or Hodgkin's disease.
      4. Temporal arteritis and polymyalgia rheumatica. Temporal arteritis as the initial manifestation of malignant histiocytosis may occur. Biopsy-proven arteritis has also been associated with follicular small cleaved-cell lymphoma, hairy-cell leukemia, lymphoplasmacytoid lymphoma, multiple myeloma, amyloidosis, and Waldenstrm's macroglobulinemia.
      5. Polymyalgia rheumatica should not prompt an extensive workup for occult malignancy above and beyond an age-appropriate malignancy assessment. Associated neoplasia is usually a chance occurrence and may involve any primary site. When polymyalgia rheumatica-like symptoms predate neoplasia, the latter is usually apparent within 3 months of onset of symptoms.

         Mimics of vasculitis associated with protean, multiorgan symptoms and signs can occur in patients with pheochromocytoma, left atrial myxoma, intravascular lymphoma, tumor emboli, and anti-cardiolipin antibodies.

      6. Anti-cardiolipin antibodies can be seen in patients with neoplasia. Anti-cardiolipin antibody syndromes are associated with thrombocytopenia and arterial or venous thrombotic events in the absence of disseminated intravascular coagulation . Such syndromes warrant consideration of underlying malignancy but probably do not justify an exhaustive search for underlying occult neoplasia.
   6. Systemic lupus erythematosus and scleroderma
      1. Systemic lupus erythematosus. There are no well-documented cases of occult malignancy presenting as SLE. Although antinuclear antibodies can be present in patients with solid neoplasms or leukemias who lack other evidence of a rheumatic syndrome, the significance of this is not understood . LE cells or antinuclear antibodies can be seen in patients with lymphoma or angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) . Diagnostic confusion may arise, as lymphadenopathy and splenomegaly are features also common in SLE.

         A lupuslike antibody syndrome, manifested by typical SLE serologic and laboratory abnormalities but lacking clinical criteria for SLE, has been associated with certain tumors and myelodysplastic disorders. For example, hypernephroma has been found in a peripartum woman , but this may have been an incidental finding because a similar lupuslike antibody syndrome can occur during pregnancy . Other tumors include gastric , cervical, and breast carcinomas, gastrointestinal lymphoma, AILD, and testicular seminoma.

         In general, a diagnosis of clinical SLE should not prompt a search for occult malignancy. However, lupuslike serology and unexplained Coombs'-positive anemia, thrombocytopenia, or circulating anticoagulants without clinical features of SLE warrant consideration of an occult neoplasm. In addition, in a patient with a known tumor who presents with pleural effusions, pericarditis, or nondeforming polyarthritis, an associated lupuslike illness should be considered.

      2. Scleroderma. Rarely, hematologic malignancies, bladder cancer, and breast or stomach carcinoma become apparent shortly after the onset of scleroderma. The scleroderma may improve following treatment of these malignancies. Carcinoid tumors are associated with scleroderma-like changes of the lower extremities. POEMS may also be associated with scleroderma-like skin changes. Scleroderma may be erroneously diagnosed before these disorders are considered.
   7. Miscellaneous. Rheumatic syndromes that may be a harbinger of neoplasia include eosinophilic fasciitis and the following disorders. Patients should be followed for development of hematologic disorders (e.g., aplastic anemia and lymphoid malignancies).
9. Reflex sympathetic dystrophy may occur secondary to brain tumor, ovarian carcinoma, or Pancoast lung tumor.
10. Erythromelalgia (burning, red, warm feet) may be associated with myeloproliferative disorders in 10% of cases.
11. Sweet's syndrome, or acute neutrophilic dermatosis, is associated with malignancy in at least 15% of cases, most commonly with acute myelogenous leukemia.
12. Palmar fasciitis and polyarthritis. Originally described in women with ovarian carcinoma, this differs from reflex sympathetic dystrophy. Palmar fasciitis and polyarthritis has also been associated with other malignancies. Plantar fasciitis may be associated with this syndrome. Polychondritis may rarely predate the discovery of a neoplasm.
13. Osteomalacia may develop in patients with a variety of benign or malignant mesenchymal tumors, giant cell tumor, hemangioma, angiosarcoma, hemangiopericytoma, neurilemmoma, and nonossifying fibroma. Epidermal nevus syndrome is also associated with this condition. Patients exhibit hypophosphatemia, normal or slightly decreased serum calcium, and usually normal serum parathyroid hormone concentrations. Abnormalities revert to normal following successful removal of tumor tissue.

    Unclassified rheumatic disorders in hospitalized patients may be associated with an underlying occult neoplasia in up to 24% of cases during a 2-year period. The frequency may be higher in men and patients over 50 years old. The malignancy is usually discovered on routine physical examination.

14. Miscellaneous musculoskeletal problems in patients with neoplasia
    1. Bone and joint infections. Patients with malignancy, especially those receiving cytotoxic therapy, are predisposed to septic complications such as pyarthrosis and osteomyelitis. Organisms include both common and opportunistic pathogens. Pyogenic arthritis caused by Streptococcus bovis or enteric organisms may signal an occult colonic neoplasm.
    2. Referred pain to the joints, neck, or back. Knee pain exacerbated by recumbency has been attributed to diffuse histiocytic lymphoma of the spinal cord. Back pain and radiculitis may be secondary to leukemic meningeal involvement or be the initial manifestation of Hodgkin's disease. Shoulder pain with normal findings on shoulder examination may be referred pain caused by infradiaphragmatic, intraabdominal neoplasms. Alternatively, intrathoracic neoplasms (e.g., Pancoast tumor) may extend into the brachial plexus and cause pain in a shoulder with a normal range of motion but evidence of muscle atrophy and loss of deep tendon reflexes.

       Mimics of vasculitis such as subacute bacterial endocarditis, cholesterol emboli, and anti-cardiolipin syndrome may occur in any patient with concomitant neoplasia.

II. Malignancies associated with an established rheumatic syndrome. The risk for certain types of cancer appears to be increased in some of the rheumatic syndromes. The increased incidence of malignancy does not appear to be related to antirheumatic therapy in the following instances:

1. Polymyositis is associated with all types of neoplasm. Although the increased risk for cancer after the diagnosis of polymyositis is consistent with cancer detection bias, clinical vigilance for associated neoplasia is indicated. Routine urinalysis , complete blood count, examination of stools for occult blood, sigmoidoscopy, mammography, prostate and testicular examinations, chest radiography, and Papanicolaou's smear are recommended screens. A more extensive search for occult malignancy may be indicated in patients at greatest risk, such as older men or patients with severe, refractory dermatomyositis.
2. RA, even in the absence of treatment with potentially oncogenic drugs, appears to be associated with an increased risk for hematologic malignancies, including lymphoma and myeloma. There is also an increased risk for leukemia in some cohorts of RA patients. In certain patients with Felty's syndrome, there is a twofold increase in total cancer incidence and a 12-fold increased risk for non-Hodgkin's lymphoma. There is also an increased risk for CD16+ large granular lymphocytes and leukemia. RA patients with secondary Sjgren's syndrome are at a 33-fold increased risk for non-Hodgkin's lymphoma. Paraproteins are an additional marker of increased risk for hematopoietic neoplasms.

   The overall risk for malignancy is reduced in some RA cohort studies. Prospective, longitudinal cohort studies of RA patients have demonstrated a lower incidence of stomach and colon carcinomas, the latter possibly related to use of nonsteroidal antiinflammatory drugs.

3. Patients with Sjgren's syndrome are at increased risk for the development of non-Hodgkin lymphoma. Waldenstrm's macroglobulinemia also appears to be more frequent in these patients. The risk is increased in both primary and secondary Sjgren's syndrome in National Institutes of Health (NIH) cohorts. In Italian studies, women with primary Sjgren's syndrome are at greatest risk. Risk factors such as disappearance of rheumatoid factor were predictive of the evolution in the NIH cohort but not in a Vanderbilt cohort.
4. Systemic sclerosis patients with pulmonary fibrosis and honeycomb lung are at increased risk for bronchoalveolar cell carcinoma.

   Discoid lupus erythematosus lesions may develop into epidermoid carcinoma. Patients with eosinophilic fasciitis are at increased risk for associated aplastic anemia and lymphoproliferative disease.

5. Immunodeficiency states. Patients with X-linked hypogammaglobulinemia, common variable immunodeficiency, ataxia-telangiectasia, and Wiskott-Aldrich syndrome are at increased risk for the development of lymphoreticular malignancy. Leukemia, medulloblastoma, and adenocarcinomas may also occur with increased frequency. Asymptomatic patients with isolated immunoglobulin A deficiency do not appear to have an increased risk for neoplasia.
6. Patients with systemic lupus erythematosus do not appear to be at increased risk for malignancy, except for neoplasia complicating cytotoxic therapy (Table 50-3).
   
   

   
   

   Table 50-3. Malignancies associated with established connective tissue disorders

   
   
   
7. Mixed cryoglobulinemia associated with vasculitis and hepatitis C was associated with non-Hodgkin's lymphoma in 14 of 200 patients. Monitoring for hepatocellular carcinoma should also be considered.
8. Paget's disease. Osteogenic sarcoma may complicate Paget's disease in 1% of patients and present with persistent, severe pain. Bone biopsy may be necessary for accurate diagnosis.
9. Multicentric reticulohistiocytosis may herald a subsequent malignancy.
10. Chronic osteomyelitis. Squamous cell carcinoma may occur in adjacent cutaneous tissue in up to 2% of cases.

III. Malignancy as a complication of antirheumatic therapy. The influence of immunosuppressive drug therapy in altering the incidence of cancer in the rheumatic population is unclear, but an increased risk for neoplasia is apparent with some regimens.

1. Alkylating agents such as cyclophosphamide and chlorambucil can increase the risk for leukemia and myelodysplastic syndromes. Cytogenetic abnormalities of chromosome 5/7 are associated with therapy-related myelodysplastic syndromes seen in rheumatic disease. In addition, cyclophosphamide is associated with bladder and other genitourinary cancers. As the latter may occur 20 years after exposure, ongoing surveillance should be considered. Sodium-2-mercaptoethane sulfate can bind the toxic metabolite acrolein and may diminish the incidence of bladder carcinoma.
2. Immunosuppressive Agents
   1. Purine antimetabolites such as azathioprine are associated with an increased risk for lymphomas and non-melanoma skin carcinomas in renal transplant recipients. The possibility of a similar increased incidence of malignancy in rheumatic disease patients treated with azathioprine remains to be firmly established. An increased incidence of non-Hodgkin's lymphoma and cervical carcinoma in SLE patients on azathioprine has been suggested. There is no apparent relationship between the amount and duration of cytotoxic therapy and the development of malignancy.
   2. Folic acid antagonists. Methotrexate, a folic acid antagonist, may rarely be associated with the development of B-cell non-Hodgkin's lymphoma in RA patients. Many, but not all, of these tumors are positive for Epstein-Barr virus. Some regress on withdrawal of the drug. Interestingly, the tumors of up to 30% of methotrexate-nave RA patients with lymphoma are positive for Epstein-Barr virus.
   3. Cyclosporine, although not mutagenic, is associated with lymphoproliferative disorders in up to 3% of renal transplantation patients treated with concomitant azathioprine and prednisone. Whether patients with rheumatic diseases who are taking cyclosporine, with or without methotrexate, have an increased risk for lymphoma and brain or skin cancers remains to be determined. In one review of more than 1,000 RA patients treated with cyclosporine, tumors developed in 17 of them.
   4. Novel or biologic agents. It remains unresolved whether agents to block tumor necrosis factor-alpha, such as Enbrel, which are available to treat refractory RA, are associated with a higher risk for non-Hodgkin's lymphoma. It also remains to be determined whether any of the other new agents with immunomodulating effects [e.g., leflunomide (Arava), mycophenolate mofetil, interleukin-10 (IL-10), or interleukin-1 receptor antagonist (IL-1ra)] will increase the relative risk for development of a malignancy in RA. Increased surveillance is certainly indicated in RA patients on combination therapies including methotrexate, anti-TNF agents and cyclosporine.
   5. Radiation therapy. Ankylosing spondylitis patients treated with spinal irradiation have an increased frequency of leukemia. The risk for myeloproliferative disorders and osseous sarcoma is likely increased in RA patients treated with total nodal irradiation.

IV. Chemotherapeutic agents that may induce rheumatic-like disorders are the following:

1. Busulfan can cause a syndrome resembling sicca syndrome.
2. Cisplatin (Platinol) has been associated with Raynaud's phenomenon .
3. Bleomycin (Blenoxane) can produce scleroderma-like features involving the skin and lungs.
4. Fluorouracil is associated with a hand- foot syndrome characterized by palmar-plantar erythrodysesthesia.
5. Anthracyclines can cause transient polyarthritis. Liposome-encapsulated doxorubicin used to treat human immunodeficiency virus-related Kaposi's sarcoma is associated with a painful hand-foot syndrome. Painful, reddened, swollen hands and feet may ulcerate, fissure, and desquamate.
6. Cytosine arabinoside (ara-C). Most vascular reactions have been noted after combination chemotherapy, but treatment with ara-C as a single agent has also been associated with necrotizing cutaneous vasculitis.
7. Any immunosuppressive therapy may predispose a patient to bone and joint infections.
8. Hormonal manipulation. Tamoxifen is reported to be associated with cases of vasculitis and polyarthritis.
9. Luteinizing hormone-releasing hormone (LHRH) agonists, such as leuprolide, buserelin, and nafarelin, and nonsteroidal anti-androgens, such as flutamide, may be associated with myalgia and arthralgias.
10. Antibacterial and antiviral agents used in the treatment of opportunistic infections may cause a variety of rheumatic problems. For example, zidovudine (AZT) is associated with a syndrome resembling dermato-myositis-polymyositis.
11. Cephalosporins are associated with serum sickness-like reactions.
12. Ciprofloxacin has been associated with tendon ruptures and flares of SLE.
13. Radiation therapy may be associated with a delayed obliterative radiation arteritis and avascular necrosis.
14. Growth factors and biologic response modifiers
    1. Granulocyte colony-stimulating factor (G-CSF) may be associated with Sweet's syndrome. Interleukins and interferons have been associated with the development of signs and symptoms of autoimmune disease or auto-antibodies. Treatment with interferon-alfa is associated with Raynaud's syndrome and SLE-like illness. The manifestations vary depending on the underlying disease being treated. When used to treat myeloproliferative disorders, interferon-alfa can induce formation of antinuclear antibodies and rheumatoid factor, polyarthritis, or polyarthralgia. The incidence for these complications appears to be much lower in patients treated for carcinoid or viral hepatitis. Ongoing clinical trials of IL-4, IL-10, IL-1ra, and other biologic response modifiers should continue to monitor for any increase in auto-antibodies or autoimmune complications.
15. Bone marrow transplantation may be associated with chronic graft -versus-host disease that includes scleroderma-like skin changes, alopecia, xerostomia, keratoconjunctivitis sicca, photosensitivity, myositis, and joint contractures.
16. Anti-thymocyte globulin is associated with a serum sickness reaction that consists of arthralgia/arthritis and a distinctive erythematous, serpiginous rash on the hands and feet at the margins of the palmar and plantar skin (moccasin distribution).
17. Intravesical therapy with bacille Calmette-Gurin for bladder cancer can be associated with a reactive or RA-like arthritis.

V. General recommendations. It is important to remain alert to the development of malignancy in any patient with a rheumatic syndrome, either as a complication of immunosuppressive therapy or secondary to the disease process itself. However, patients who require special attention or surveillance for malignancy include those on/with:

1. Hypertrophic osteoarthropathy.
2. Dermatomyositis or polymyositis.
3. Cytotoxic or immunosuppressive therapy.
4. Immunodeficiency states (patients with lupuslike serology and unexplained Coombs'-positive anemia, thrombocytopenia, or circulating anticoagulants without clinical features of SLE).
5. Hepatitis C-associated mixed cryoglobulinemia/vasculitis.

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Books@Ovid
Copyright 2000 by Lippincott Williams & Wilkins
Stephen A. Paget, M.D., Allan Gibofsky, M.D., J.D. and John F. Beary, III, M.D.
Manual of Rheumatology and Outpatient Orthopedic Disorders