데일리메디 Chemotherapy-related Arthropathy

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Chemotherapy-related Arthropathy


[ 2006년 10월 23일 01시 32분 ]

ABSTRACT
Purpose: Rheumatic manifestations may develop in patients who receive chemotherapy. We examined the characteristics of chemotherapy-related arthropathy in cancer patients.
Materials: There were 18 patients who developed joint symptoms after receiving chemotherapy. We reviewed their charts to obtain the demographic information, the underlying tumor, the chemotherapeutic agents, the rheumatologic symptoms and the laboratory findings. Each patient was interviewed by telephone about his or her current joint symptoms.
Results: The patients were 14 females and 4 males and their mean age was 53.9 ± 10.6 years. There were five breast cancers, three advanced gastric cancers and lung cancers, two colon and cervix cancers, a lymphoma, a glioblastoma and a bladder tumor. 5-fluorouracil, cyclophosphamide and cisplatin were most common drugs. The joint symptoms usually began six months after the first session of chemotherapy. They had on average eight tender joints, and six hours of morning stiffness. Five patients showed positive anti-nuclear antibody and two had rheumatoid factor. NSAID and DMARD were prescribed. Five patients were not improved, so they also received low dose oral corticosteroids. For the 15 patients who could be followed up, 14 patients showed favorable responses that were characterized by a significant decrease (more than 50%) in morning stiffness, pain and tender joint counts after a mean 3 months of treatment. Nine patients had complete resolution of symptoms and stopped all medications.
Conclusions: Chemotherapy-related arthropathy is not rare and the prognosis is fairly good with early treatment using DMARD and corticosteroids.
--------------------------------------------------------------------------------Key words; cancer, chemotherapy, arthritis, treatment

Introduction
The rheumatic manifestations associated with malignancy have been well documented, although many of the associations are based on only a small numbers of case reports and series reports1-5. These manifestations may be due to the direct invasion of the joints and muscles by the tumor, paraneoplastic syndrome induced by a distant tumor via the humoral factors, altered immune surveillance that causes both rheumatic and neoplastic disease and adverse reactions to the anticancer therapy.
Several rheumatic manifestations may develop in patients after their chemotherapy for the treatment of malignancy. There are reports on the development of RA, Reiter’s syndrome and vasculitis in patients undergoing immunotherapy or radiotherapy, and for the exacerbation of RA after chemotherapy6-9. Additionally, postchemotherapy rheumatism has been described in the patients who were treated for breast cancer, ovarian cancer and non-Hodgkin lymphoma10-15. The phenomenon has been described as a temporary noninflammatory, self-limiting, migratory musculoskeletal pain syndrome. Characteristically, the stiffness, arthralgia and arthritis involve both the large and small upper and lower extremity joints, and this develops within a few months after the completion of combination chemotherapy. These symptoms can occur without the evidence of metastatic disease and without the positive laboratory and radiologic findings that are indicative of rheumatic disease.
Though these chemotherapy-related joint symptoms has been related to treatment of cancer, the evidence has been limited because most of the previous reports were single or multiple cases having very restricted cancer patients such as breast cancer. Therefore, we examined the occurrence and prognosis of chemotherapy-related arthropathy in a variety of cancer patients in a limited time period.

Patients and Methods
The subjects of our study were 18 patients who were referred to the arthritis center at Ajou University Hospital from Jan. 2002 to Jul. 2003 due to their newly developed or aggravated preexisting joint symptoms during chemotherapy. The predominant complaint was stiffness upon arising after periods of inactivity, and myalgia and arthralgia during the adjuvant or palliative systemic chemotherapy and also after the completion of chemotherapy.
We reviewed their charts to obtain demographic information as well as information about the underlying tumor, the dates of the initiation and discontinuation of systemic chemotherapy, the chemotherapeutic regimen and the other treatment such as radiotherapy and/or operation. These 18 patients had no evidence of metastatic cancer at the time of their evaluation. The clinical exam was performed by a rheumatologist (CHS). We asked about the duration of morning stiffness, and their subjective pain intensity was evaluated by using a 10 cm visual analog pain scale (VAPS). Joint tenderness and swelling were assessed in 44 joints and the pain on passive motion was evaluated in hip joints. Arthritis was verified with the evidence of joint inflammation such as joint tenderness and swelling; otherwise arthralgia was considered. As a laboratory parameter, we documented positivity for RF and ANA, and the inflammatory markers such as ESR and CRP at the initial visit. Also, the patients had X-rays taken of their hands and feet. The patients were treated according to the clinical judgement of the rheumatologist rather than by an algorithm. Because several of the reports about chemotherapy-related joint symptoms showed that treatment with only NSAID was not adequate for controlling the joint symptoms, our patients were initially managed with NSAID and DMARD if there is evidence of joint inflammation. He then added low dose corticosteroids if the joint symptoms were not improved after 2 weeks. The medication was tapered and eventually discontinued if the joint symptoms disappeared. Finally, each patient was interviewed by telephone for 10-20 minutes after giving their verbal consent. They were questioned about the duration, resolution and change in the severity of their joint symptoms, with special attention being given to the relationship with the administration of medications.

Results
Patients were 14 female and 4 male patients and their mean age was 53.9 ± 10.6 years (age range: 27-72 years) and the mean follow up duration was 21.5 ± 22.3 weeks (range: 4 - 64 weeks). Patients had various cancers; five breast cancers, three advanced gastric cancers and lung cancers, two colon cancers and cervix cancers, a lymphoma, a glioblastoma and a bladder cancer (Table 1). Ten patients received radiation therapy during and after combination chemotherapy. Twelve patients had undergone surgical removal of their tumor. Three patients received only palliative chemotherapy. Diverse chemotherapeutic agents were used for the adjuvant and palliative chemotherapy. 5 fluorouracil (FU) was the most commonly used drug. Cyclophosphamide, cisplatin, doxorubicin, mitomycin-C and paclitaxel were also common drugs. All the drugs were administered intravenously with a mean four weeks cycle. For antiemetics, all patients received 5-HT3 antagonist and metoclopramide intravenously on each day of their chemotherapy, and eleven patients were administered steroids intravenously.
Sixteen patients did not have any symptoms prior to the administration of chemotherapy, and two patients had experienced a significant exacerbation of previous symptoms as well as additional new symptoms. One patient (patient No. 8) had arthralgia of the right fingers and she developed morning stiffness and pain in both her knees and shoulders. The other patient (No. 16) had an arthralgia of all fingers for 10 years and his joint symptoms were aggravated and spread to both wrists, both feet and both temporomandibular joints. The joint symptoms usually began 6 ± 3 months (range: 1-14 months) after the first session of chemotherapy (Table 2). Ten patients’ symptoms began within 5 months after the last session of chemotherapy and eight patients’ symptoms began during chemotherapy, with 4 patients’ symptoms occurring within 4 months after the first secession of chemotherapy. They complained of 6 hours of morning stiffness (range; 0-24 hours) and they had, on average, 8 tender joints (range; 2-14 joints). The commonly involved joints were fingers, toes, shoulders and knees (Table 3). Fourteen patients showed a symmetrical distribution. Four patients complained of joint pain without having any evidence of joint inflammation such as tenderness and swelling, so these patients had arthralgia without arthritis. Fourteen patients had arthritis: there were 11 cases of polyarthritis and 3 cases of pauciarthritis. Most patients showed nearly normal inflammatory markers on the laboratory tests: the mean ESR was 21.6 ± 14.4 mm/hr (range: 0-47), and the mean CRP was 0.27 ± 0.4 mg/dL (range: 0.02-1.18). Five patients had a positive ANA test and 2 had a positive RF test. For the 5 patients who had a positive ANA test, 2 patients (No.1 and 18) discontinued their medication because their symptoms were completely resolved and 1 patient (No.15) had only a partial resolution of symptoms with NSAIDs. Of the 2 patients who had RF, one patient (No. 4), who showed only partial resolution of the symptoms with NSAID and DMARD, had complete resolution of symptoms after receiving additional low dose oral corticosteroids, but her symptoms returned with a greater severity after she voluntarily stopped the corticosteroids. Five patients satisfied the ACR criteria for RA: 2 patients had their medication stopped due to complete resolution of the joint symptoms, 1 patients showed partial resolution of joint symptoms, 1 patient expired, and 1 patient was lost to follow up.
Among the 18 patients, fifteen completed the study and three patients were lost to follow up. One patient expired and 2 patients were lost due to their continuous pain, who tried complementary and alternative medicine. All the patients initially received NSAID and/or DMARD. Five patients were not improved with these medications, so they received additional low dose oral corticosteroid. Of the 15 patients who were followed up, 14 patients showed favorable responses that were characterized by a significant decrease (more than 50%) in duration of morning stiffness, VAPS and the tender and swollen joint counts at a mean period of 3 months (range: 1-6 months) after the treatment, and one patient (No 17) did not. Among them, 9 patients had complete resolution of joint symptoms and their medication stopped by us due to the resolution of their pain or they did so voluntarily. Five patients had decreased joint symptoms with the medications, but they still needed the medications.

Discussion
Various musculoskeletal manifestations can develop in a patient after the administration of chemotherapy for the treatment of malignancy. We identified 18 patients who, after starting chemotherapy, had arthritis or arthralgia in a relatively short period, about 19 months. Among these, 16 patients did not have any symptoms prior to the administration of chemotherapy, and two patients had experienced a significant exacerbation of their previous symptoms, as well having developed additional new symptoms. The half of patients developed joint symptoms during chemotherapy and the others developed their symptoms within 5 months after the last bout of chemotherapy. The joint symptoms were well controlled by NSAID and DMARD with/without corticosteroid in most patients, but not in some of the patients.
The musculoskeletal symptoms after the administration of chemotherapy were first reported as postchemotherapy rheumatism by Loprinzi et al10. They described eight patients who developed joint symptoms in 1-2 months after adjuvant chemotherapy for breast cancer with a regimen comprised of cyclophosphamide, methotrexate and 5-FU. Treatment with NSAIDs was ineffective, but those symptoms abated in most of the patients within 1 year. Other authors have also reported similar cases for breast cancer, ovarian cancer and lymphoma11-15. There are several differences between the patients who had postchemotherapy rheumatism and our patients.
The first is that our patients were more heterogeneous for the type of malignancy and the chemotherapeutic regimens. Although breast cancer was the most common tumor, gastric cancer, lung cancer, colon cancer, cervix cancer, lymphoma, glioblastoma and bladder cancer were found. Also, various chemotherapeutic agents were involved such as 5FU, cyclophosphamide, cisplatin, doxorubicin, mitomycin-C, paclitaxel and others. These findings suggest that musculoskeletal symptoms may develop independent of the type of cancer and the chemotherapeutic agents.
The second difference is the time for developing the joint symptoms. All the patients with postchemotherapy rheumatism developed arthralgia in a short period after finishing the chemotherapy. However, half of our patients had joint symptoms during chemotherapy and 4 patients complained of this within 4 months after the first session of chemotherapy. This temporal relationship strongly suggests that chemotherapy can induce joint symptoms.
The third difference is our patients showed definite evidence of joint inflammation such as tenderness and swelling, but the description of postchemotherapy rheumatism in the previous study was vague about joint inflammation, and some of the patients with postchemotherapy rheumatism had fibromyalgia-like symptoms. We designated our patents as chemotherapy-related arthropathy because of the differences from the postchemotherapy rheumatism and there was definite evidence of joint inflammation. For chemotherapy-related arthropathy, the clinical manifestations were similar to RA, such as morning stiffness, polyarthritis, frequent involvement of fingers and toes, and the symmetric distribution. However, there were some differences from RA; only 2 patients showed a positive RF test, only 5 patients satisfied the ACR criteria for RA and the inflammation markers were normal in most of our patients.
The fourth difference is the response to treatment and the prognosis. All the patients with postchemotherapy rheumatism did not respond to NSAID and their response was variable to corticosteroid, but the symptoms resolved spontaneously in most the patients within 1 year. For our patients, however, 14 patients among the 15 patients who could be followed up responded to NSAID and DMARD with or without corticosteroid. The response was rapid, as early as 1 month with medication, and the response time ranged up to 8 months. Nine patients were completely free of joint symptoms and 5 patients still complained of arthralgia even with receiving medication. Another 4 patients were not improved with medication; 2 patients were lost to follow up due to the continuous joint symptoms and 1 patient expired. It seems likely that the complete resolution of pain in most of our patients was a result of the initial administration of DMARDs. We used a variety of DMARDs: hydroxychloroquine, sulfasalazine, bucillamine and methotrexate. For some patients who showed an unsatisfactory response, adding corticosteroid resulted in improving the joint symptoms. An important matter for the management of chemotherapy-related arthropathy is early detection and the early administration of NSAID and DMARD with/without corticosteroids.
The pathophysiologic mechanisms of chemotherapy-related arthropathy remain uncertain. There is a suggestion that combination chemotherapy may disturb the immune system profoundly enough as to break the self-tolerance of a patient, which produces autoantibodies and musculoskeletal manifestations16. This idea is supported by a report that gonadal ablation by chemotherapy can result in thymic hyperplasia and altered thymic function that leads to autoimmunity17. In our patients, 5 had a positive ANA tests and 2 had a positive RF tests. The development of rheumatic symptoms in patients being treated with tamoxifen has been described18. Several observations suggest that tamoxifen may induce or exacerbate arthritis through its antiestrogen effect15. It is possible that chemotherapy and tamoxifen may induce gonadal atrophy, and this result in T cell activation and autoimmune manifestations.
The development of chemotherapy-related arthropathy is not a rare event and the physician’s awareness of this syndrome is important. The physician’s awareness of this syndrome may limit the need for extensive work-ups to exclude recurrent cancer or other rheumatologic diseases. The most important point is that early diagnosis and early treatment lead to a better prognosis.

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