Methotrexate in Patients With Scleroderma/CREST Syndrome
Is there any benefit of using methotrexate in patients with arthralgias in scleroderma/CREST syndrome?
Sabiha Shahnaz, MD
Methotrexate (MTX) can be used to control arthralgias in scleroderma (progressive systemic sclerosis, PSS) patients in a manner analogous to the use of MTX for rheumatoid arthritis and other autoimmune disorders. MTX, as well as other disease-modifying antirheumatic drugs (DMARDs), have been used successfully to spare corticosteroids in patients with myositis features.
Comment
PSS often starts with arthralgias, myalgias, and puffiness of the skin. Features of early arthritic symptoms may include tendon friction rubs. Sclerotic skin may also contribute to limiting joint motion and the development of joint contractures.
As an initial therapy, PSS patients may require significant analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs). Low-dose steroids often can control the pain and stiffness. However, if higher-dose steroids are required, they may enhance the risk of developing renal complications as well as other steroid-related side effects.
Physical therapy is important in limiting contractures (which can occur quite rapidly). Therapy should include both active and passive exercises. Adequate analgesia may be required to permit a regular daily regimen. Encouragement from the therapist and physician is also critical if a regular program is to be performed.
In patients who have significant gastrointestinal problems, MTX can be administered by self-injection. Patients who continue to have nausea associated with MTX may get some relief with an H2 blocker or proton-pump inhibitor. This drug is usually cycled in a weekly manner with MTX; it is used at 3 tablets per week, including the evening before, the day of, and the morning after the weekly MTX dose.
Folic acid at a dose of 1 mg/day should be given routinely to all patients taking MTX. The dose may be increased to 5 mg/day as needed, on the basis of reporting of residual symptoms.
Folinic acid should only be used in patients who have not had a satisfactory response to folic acid. Folinic acid is considerably more expensive than folic acid, and dosing is critical in both preventing toxicity and maintaining the efficacy of MTX. A typical dose is 2.5-5 mg given once weekly, 8-12 hours after MTX administration.
In addition to arthralgias, mild myopathy with little biochemical or histologic change is a common feature of systemic sclerosis. A smaller group of patients have an inflammatory myopathy. In the latter group, proximal weakness and other features, such as elevation of serum muscle enzymes (creatine kinase, aldolase, and aminotransferases), abnormal electromyography, magnetic resonance imaging, and muscle biopsy findings, are indistinguishable from idiopathic inflammatory myopathy (polymyositis). The treatment of myopathy in either dermatomyositis or PSS includes MTX, azathioprine, or other DMARDs.
Common toxicities associated with MTX include gastrointestinal problems such as nausea, stomach upset, and loose stools; stomatitis or soreness of the mouth; macular punctate rash that usually occurs on the extremities; central nervous system problems including headache, fatigue, or impaired ability to concentrate; alopecia; and fever.
MTX hepatotoxicity is perhaps the most common serious side effect. MTX can induce a variety of histologic changes, including steatosis, stellate (Ito) cell hypertrophy, anisonucleosis (nuclei of varying sizes), and hepatic fibrosis.
In addition, MTX-induced interstitial lung disease (ILD) could potentially mimic the ILD associated with PSS. ILD is most likely to occur within the first 2 years of MTX therapy, and the index of suspicion should be increased during this period. The drug should be temporarily discontinued and a chest radiograph should be performed in any patient who complains of nonproductive cough and dyspnea without other symptoms of a viral illness. MTX should be permanently discontinued in a patient with respiratory symptoms and a new interstitial pattern on chest radiograph; such patients can be started on another DMARD, such as azathioprine. A course of corticosteroids may be beneficial in patients with severe reaction to DMARDs (with careful attention to the possibility of provoking scleroderma renal crisis).
Hematologic toxicity in association with MTX includes macrocytic red blood cells, but a more serious abnormality is the development of pancytopenia. In an attempt to prevent these complications, the American College of Rheumatology suggests that a routine peripheral blood count should be performed every 3 months while on MTX.
Is there any benefit of using methotrexate in patients with arthralgias in scleroderma/CREST syndrome?
Sabiha Shahnaz, MD
Methotrexate (MTX) can be used to control arthralgias in scleroderma (progressive systemic sclerosis, PSS) patients in a manner analogous to the use of MTX for rheumatoid arthritis and other autoimmune disorders. MTX, as well as other disease-modifying antirheumatic drugs (DMARDs), have been used successfully to spare corticosteroids in patients with myositis features.
Comment
PSS often starts with arthralgias, myalgias, and puffiness of the skin. Features of early arthritic symptoms may include tendon friction rubs. Sclerotic skin may also contribute to limiting joint motion and the development of joint contractures.
As an initial therapy, PSS patients may require significant analgesia with acetaminophen and/or nonsteroidal anti-inflammatory drugs (NSAIDs). Low-dose steroids often can control the pain and stiffness. However, if higher-dose steroids are required, they may enhance the risk of developing renal complications as well as other steroid-related side effects.
Physical therapy is important in limiting contractures (which can occur quite rapidly). Therapy should include both active and passive exercises. Adequate analgesia may be required to permit a regular daily regimen. Encouragement from the therapist and physician is also critical if a regular program is to be performed.
In patients who have significant gastrointestinal problems, MTX can be administered by self-injection. Patients who continue to have nausea associated with MTX may get some relief with an H2 blocker or proton-pump inhibitor. This drug is usually cycled in a weekly manner with MTX; it is used at 3 tablets per week, including the evening before, the day of, and the morning after the weekly MTX dose.
Folic acid at a dose of 1 mg/day should be given routinely to all patients taking MTX. The dose may be increased to 5 mg/day as needed, on the basis of reporting of residual symptoms.
Folinic acid should only be used in patients who have not had a satisfactory response to folic acid. Folinic acid is considerably more expensive than folic acid, and dosing is critical in both preventing toxicity and maintaining the efficacy of MTX. A typical dose is 2.5-5 mg given once weekly, 8-12 hours after MTX administration.
In addition to arthralgias, mild myopathy with little biochemical or histologic change is a common feature of systemic sclerosis. A smaller group of patients have an inflammatory myopathy. In the latter group, proximal weakness and other features, such as elevation of serum muscle enzymes (creatine kinase, aldolase, and aminotransferases), abnormal electromyography, magnetic resonance imaging, and muscle biopsy findings, are indistinguishable from idiopathic inflammatory myopathy (polymyositis). The treatment of myopathy in either dermatomyositis or PSS includes MTX, azathioprine, or other DMARDs.
Common toxicities associated with MTX include gastrointestinal problems such as nausea, stomach upset, and loose stools; stomatitis or soreness of the mouth; macular punctate rash that usually occurs on the extremities; central nervous system problems including headache, fatigue, or impaired ability to concentrate; alopecia; and fever.
MTX hepatotoxicity is perhaps the most common serious side effect. MTX can induce a variety of histologic changes, including steatosis, stellate (Ito) cell hypertrophy, anisonucleosis (nuclei of varying sizes), and hepatic fibrosis.
In addition, MTX-induced interstitial lung disease (ILD) could potentially mimic the ILD associated with PSS. ILD is most likely to occur within the first 2 years of MTX therapy, and the index of suspicion should be increased during this period. The drug should be temporarily discontinued and a chest radiograph should be performed in any patient who complains of nonproductive cough and dyspnea without other symptoms of a viral illness. MTX should be permanently discontinued in a patient with respiratory symptoms and a new interstitial pattern on chest radiograph; such patients can be started on another DMARD, such as azathioprine. A course of corticosteroids may be beneficial in patients with severe reaction to DMARDs (with careful attention to the possibility of provoking scleroderma renal crisis).
Hematologic toxicity in association with MTX includes macrocytic red blood cells, but a more serious abnormality is the development of pancytopenia. In an attempt to prevent these complications, the American College of Rheumatology suggests that a routine peripheral blood count should be performed every 3 months while on MTX.