70-Year-Old Woman With Rash and Muscle Weakness

Abstract

A 70-year-old woman presented to our institution for a second opinion regarding a 6-month history of progressive swelling, rash, and muscle weakness. She first noted facial swelling 6 months previously that later progressed to involve all her extremities. A month later, a mildly pruritic erythematous rash developed on her upper chest that worsened with sun exposure. She was seen by a dermatologist in her home community, and topical corticosteroids were initiated without improvement. During the next few months, she noted cramping and weakness in her neck muscles that gradually evolved to include her shoulders, pelvis, and thighs. She found it difficult to rise from a chair, ascend stairs, or comb her hair. She also experienced recent difficulty swallowing solid foods. The patient's medical history included hypertension and hyperlipidemia. Atorvastatin was discontinued 3 months before presentation to our institution because of concern about possible drug-induced myopathy. She had no family history of musculoskeletal disease. 1.On the basis of the clinical presentation, which one of the following diagnoses is most likely in our patient? a.Muscular dystrophyb.Polymyositis (PM)c.Dermatomyositis (DM)d.Myasthenia gravise.Polymyalgia rheumatica This patient's proximal muscles were weak, referred to as limb-girdle weakness. Muscular dystrophy, PM, and DM can cause this clinical pattern. Muscular dystrophy is unlikely in our patient because it develops slowly (over years rather than weeks or months) and rarely presents in patients older than 30 years. Polymyositis is an idiopathic inflammatory myopathy that usually presents as symmetrical pain and weakness of the proximal limbs and neck flexor muscles but without the type of rash seen in our patient. Dermatomyositis is an idiopathic inflammatory myopathy similar to PM but is associated with a rash and therefore is the most likely diagnosis in our patient. Myasthenia gravis is an autoimmune disorder that affects the neuromuscular junction and is characterized clinically by weakness of skeletal muscles and fatigability on exertion. The cranial muscles are affected first, and diplopia and ptosis are common initial complaints, features our patient did not have. Polymyalgia rheumatica is characterized by severe pain and stiffness of the proximal muscles, but strength is usually unaffected, unlike this patient's clinical presentation. On physical examination, the patient had considerable swelling of her face and extremities. She had a pinkish, confluent flat rash around her neck and upper chest. Cranial nerves were intact. Muscle strength was particularly diminished in the hip flexors and shoulder abductors but relatively normal elsewhere. Deep tendon reflexes were normal. The abdomen was slightly distended with some shifting dullness. There was no obvious hepatosplenomegaly. Laboratory tests yielded the following results (reference ranges shown parenthetically): hemoglobin, 11.6 g/dL (12.0-15.5 g/dL); erythrocyte sedimentation rate, 20 mm/h (0-29 mm/h); albumin, 2.5 g/dL (3.5-5.0 g/dL); alanine aminotransferase, 37 U/L (9-29 U/L); aspartate aminotransferase, 105 U/L (12-31 U/L); creatine kinase (CK), 988 U/L (38-176 U/L); lactate dehydrogenase, 363 U/L (112-257 U/L); aldolase, 11.1 U/L (<7.4 U/L); antinuclear antibody, 0.5 (<1.0); and rheumatoid factor, 27 IU/mL (<15 IU/mL). 2.Which one of the following studies would be most specific in confirming the suspected diagnosis in our patient? a.Magnetic resonance imagingb.Electromyography (EMG)c.Skin biopsyd.Muscle biopsye.Myositis-specific antibody testing Magnetic resonance imaging can detect muscle inflammation and may guide the selection of a muscle biopsy site, especially when muscle weakness is minimal or patchy. However, it cannot differentiate DM from other inflammatory conditions. Electromyography typically shows increased membrane irritability in the form of a classic triad: spontaneous fibrillations, abnormal low-amplitude polyphasic motor potentials, and bizarre high-frequency discharges. Abnormalities on EMG are supportive, but not diagnostic, of DM. Often, EMG can help localize the best site to obtain a muscle biopsy. Histopathologic examination of DM skin lesions reveals an atrophic vacuolar interface dermatitis, which is characteristic of DM but can also be seen in lupus erythematosus. Muscle biopsy is the most specific and definitive study for diagnosing inflammatory myopathy. In PM, T cells infiltrate the muscle fasciculi and surrounding individual healthy muscle fibers, resulting in phagocytosis and necrosis. In DM, the inflammation is predominantly perivascular and around, rather than within, the muscle fasciculi. Muscle necrosis occurs at the periphery of the muscle bundle, resulting in perifascicular atrophy, pathognomonic of DM. Myositis-specific antibodies are autoantibodies directed against RNA synthetases, ribonucleoproteins, and certain nuclear antigens. These autoantibodies are present in only about a third of inflammatory myopathies and are of uncertain pathogenetic importance. Our patient was evaluated further with a dermatology consultation. Skin biopsy showed thinning of the epidermis and presence of vacuolated basal cells, consistent with atrophic vacuolar interface dermatitis. Electromyography revealed short-duration, low-amplitude, frequently polyphasic motor unit potentials in all muscles tested, with spontaneous fibrillation potentials in the proximal muscles. The patient was tested for the presence of myositis-specific antibodies. Test results were negative for anti-Jo-1 antibody. Rheumatology consultation recommended that a muscle biopsy be performed as well as cancer work-up. 3.Which one of the following cancer screening studies is the least useful in our patient? a.Transvaginal ultrasonographyb.Serum CA 125c.Urinalysisd.Colonoscopye.Chest radiography Numerous types of malignancies have been associated with DM, which can manifest as part of a paraneoplastic syndrome. Although not part of a routine cancer screening evaluation, transvaginal ultrasonography and serum CA 125 measurement are indicated in women with DM because of their increased risk of ovarian cancer. Urinalysis, although the least costly among the studies listed, is of little value because bladder and kidney cancer are not commonly associated with DM. Furthermore, microhematuria can be seen in healthy individuals and is not specific for malignancy. Colorectal cancer is associated with DM in elderly patients, and many experts favor colonoscopy over fecal occult blood tests. Chest radiography is useful because of the common association of lung cancer in patients with DM. The serum CA 125 level was markedly elevated at 1575 U/mL (<35 U/mL). Pelvic ultrasonography revealed a solid mass (12 × 12 × 13 cm) arising within the pelvis, which was confirmed by computed tomography (CT). Muscle biopsy was deferred, and the patient underwent exploratory laparotomy, which revealed an extensive tumor arising from the right ovary with multiple metastases to the small and large bowels. Bilateral salpingo-oophorectomy, omentectomy, pelvic lymphadenectomy, and generalized tumor cytoreduction were performed. Pathologic examination confirmed a high-grade endometrioid-type ovarian adenocarcinoma. Medical oncology consultation recommended treatment with carboplatin and paclitaxel. Prednisone was initiated at a dosage of 1 mg/kg for treatment of DM. Our patient was transferred to the physical medicine and rehabilitation hospital service for convalescence. By this time, her muscles were profoundly weak, and she required assistance with most of her activities of daily living. The patient continued to experience muscular weakness despite corticosteroid treatment and physical therapy. A thyroid panel yielded the following results: thyroid-stimulating hormone (TSH), 6.8 mIU/L (0.3-5.0 mIU/L); free thyroxine (T4), 1.2 ng/dL (0.8-1.8 ng/dL); and triiodothyronine (T3), 120 ng/dL (80-180 ng/dL). 4.Which one of the following statements best describes the thyroid findings in our patient? a.This patient has nonthyroidal illness and does not need thyroid hormone replacementb.This patient's TSH level is falsely elevated because of corticosteroid usec.If the serum reverse T3 (rT3) level were measured in this patient, it would likely be elevatedd.This patient has subclinical hypothyroidism and would likely benefit from thyroid hormone replacemente.This patient has subclinical hypothyroidism but would probably not benefit from thyroid hormone replacement Generally, thyroid function should not be assessed in hospitalized patients because of the high prevalence of nonthyroidal illness, which usually manifests as a low T3 level alone, low T3 and free T4 levels, and in severe cases, low T3, free T4, and TSH levels. Although the TSH level may be elevated transiently during the recovery phase, serum T3 and free T4 levels would be low. A high TSH level in the setting of normal T3 and free T4 levels is not compatible with nonthyroidal illness. Corticosteroids reduce, not increase, serum TSH levels. Reverse T3 is the product of 5′-monodeiodination of T4. Serum rT3 concentrations are usually high in patients with nonthyroidal illnesses because of inhibition of 5′-monodeiodinase activity, resulting in reduced metabolism of rT3 to diiodothyronine and increased conversion of T4 to rT3. In intrinsic hypothyroidism, rT3 levels tend to be normal. Subclinical hypothyroidism is defined as an elevated TSH level with a normal free T4 level, as in our patient. Data from several recent randomized trials have shown no benefit in treating such patients in terms of lipid levels, cardiovascular disease, and quality of life. Furthermore, there is strong evidence that thyroid hormone replacement results in overtreatment in a substantial proportion of patients with subclinical hypothyroidism. Thus, it is unlikely that our patient would benefit from thyroid hormone replacement. Over the next few weeks, our patient's functional status continued to decline. She eventually developed dysphagia, and a percutaneous endoscopic gastrostomy tube was placed to achieve better nutrition. A repeated CK measurement was 703 U/L. Concerns about this patient's prognosis were raised. 5.Which one of the following findings would not predict a poor outcome in our patient? a.Elevated CK levelb.Delayed diagnosis and treatment of DMc.Severe muscle weaknessd.Dysphagiae.Associated malignancy An elevated CK level does not predict a poor outcome or a poor response to treatment. The lack of its predictive value may reflect the sequential changes in CK levels that can occur during the course of the disease (ie, maximal elevation early in the disease with a decrease thereafter due to progressive muscle damage). Delayed treatment of DM is a predictor of poor outcome. Fafalak et al1Fafalak RG Peterson MG Kagen LJ Strength in polymyositis and dermatomyositis: best outcome in patients treated early.J Rheumatol. 1994; 21: 643-648PubMed Google Scholar examined muscle strength over the course of 2½ years in 65 patients with DM or PM and found that those treated within 6 months of disease onset had better outcomes than those with later treatment initiation. Severe muscle weakness and dysphagia are both associated with a reduced chance of survival. Several studies have shown that an associated malignancy is an independent predictor of poor outcome. Chemotherapy was initiated. Our patient received 2 courses of carboplatin and paclitaxel without serious adverse effects. During her second week of treatment, she became acutely hypoxic and was found to have a pulmonary embolism. She was transferred to the medical intensive care unit for respiratory distress and underwent biphasic positive airway pressure. The next morning, the patient and her family expressed their desire to withdraw care. She died of respiratory failure later that day. This patient presented with classic signs and symptoms of DM, a rare autoimmune disorder manifested by a symmetrical proximal inflammatory myopathy and a characteristic cutaneous eruption. The term polymyositis refers to a condition that spares the skin. In 1975, Bohan and Peter2Bohan A Peter JB Polymyositis and dermatomyositis (first of two parts).N Engl J Med. 1975; 292: 344-347Crossref PubMed Scopus (3770) Google Scholar proposed a set of criteria to help diagnose and classify PM and DM. Four of these criteria relate to the muscle disease: progressive proximal weakness, elevated plasma muscle enzyme values, abnormal EMG results, and abnormal muscle biopsy findings. The fifth criterion relates to cutaneous findings. At the time these criteria were developed, DM and PM were thought to differ only by the presence or absence of cutaneous disease. We now know that these disorders are pathogenetically different. Dermatomyositis is associated with immune complex deposition in the vessels, whereas PM reflects direct T-cell-mediated muscle injury. The association between DM and malignancy has been suspected since the first case report of DM and concurrent gastric carcinoma published in 1916. In 1976, Barnes and Mawr3Barnes BE Mawr B Dermatomyositis and malignancy: a review of the literature.Ann Intern Med. 1976; 84: 68-76Crossref PubMed Scopus (365) Google Scholar reviewed 258 cases of DM and cancer and reported that the cancer rate in these patients was 5 to 7 times that in the general population. However, the authors conceded that definitive statistical significance was precluded by the lack of control populations. Two subsequent population-based studies provided conflicting results. A Mayo Clinic study of 115 index patients with PM-DM found a slight increase of malignant disease (25%) compared with matched controls (17%), but this difference was not statistically significant.4Lakhanpal S Bunch TW Ilstrup DM Melton III, LJ Polymyositis-dermatomyositis and malignant lesions: does an association exist?.Mayo Clin Proc. 1986; 61: 645-653Abstract Full Text Full Text PDF PubMed Scopus (151) Google Scholar The authors argued that the slight increase in cancer among patients with PM-DM was explained by referral bias. A Canadian study from 1965 to 1980 of 71 patients with PM-DM found a higher prevalence of antecedent or concurrent cancer in the PM-DM group (15/71) compared with the control group (5/71), but cohort analysis through 1981 showed no increase in the number of subsequent malignancies in patients with PM-DM compared with the age- and sex-matched general population.5Manchul LA Jin A Pritchard KI et al.The frequency of malignant neoplasms in patients with polymyositis-dermatomyositis: a controlled study.Arch Intern Med. 1985; 145: 1835-1839Crossref PubMed Scopus (128) Google Scholar Since the publication of those studies, 2 large population studies have confirmed an association between cancer and DM and, to a lesser extent, PM. A Swedish study using data from the national disease registry found an incidence of malignancy in 15% of 392 patients with DM (relative risk of 2.4 in men and 3.4 in women).6Sigurgeirsson B Lindelof B Edhag O Allander E Risk of cancer in patients with dermatomyositis or polymyositis: a population-based study.N Engl J Med. 1992; 326: 363-367Crossref PubMed Scopus (683) Google Scholar Among 396 patients with PM, the incidence of cancer was 9% (relative risk of 1.7 in men and 1.8 in women). An Australian study examined data from 537 patients with biopsy-proven inflammatory myopathy.7Buchbinder R Forbes A Hall S Dennett X Giles G Incidence of malignant disease in biopsy-proven inflammatory myopathy: a population-based cohort study.Ann Intern Med. 2001; 134: 1087-1095Crossref PubMed Scopus (354) Google Scholar After adjustment for age and sex, the risk of malignant disease was estimated to be increased 6-fold in patients with DM and 2-fold in patients with PM compared with the general population. Dermatomyositis is most strongly associated with ovarian, pulmonary, gastric, colorectal, and pancreatic cancers and non-Hodgkin lymphoma, whereas PM is strongly associated with pulmonary and bladder cancer and non-Hodgkin lymphoma.8Hill CL Zhang Y Sigurgeirsson B et al.Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.Lancet. 2001; 357: 96-100Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar In almost two thirds of patients, a close temporal relationship exists between the diagnosis of myositis and the diagnosis of malignancy, suggesting that DM may be a paraneoplastic manifestation. Recommendations on the extent and duration of cancer screening in patients with DM have changed in the past decade. In patients without a personal or family history of malignancy, screening has usually been limited to a complete blood cell count, erythrocyte sedimentation rate, liver function tests, serum calcium concentration, chest radiography, and fecal occult blood tests.9Callen JP When and how should the patient with dermatomyositis or amyopathic dermatomyositis be assessed for possible cancer? [editorial].Arch Dermatol. 2002; 138: 969-971Crossref PubMed Scopus (55) Google Scholar In women, screening has also included serum CA 125 determination, pelvic ultrasonography, and mammography. Recently, some authorities have advocated more aggressive screening measures. Because colon cancer constitutes a large proportion of the malignancies in patients older than 65 years, routine colonoscopy in these patients has been recommended. Additionally, Sparsa et al10Sparsa A Liozon E Herrmann F et al.Routine vs extensive malignancy search for adult dermatomyositis and polymyositis: a study of 40 patients.Arch Dermatol. 2002; 138: 885-890Crossref PubMed Google Scholar have advocated routine thoracoabdominal CT imaging for men and thoracoabdominalpelvic CT imaging for women. This recommendation is based on results of their retrospective study of malignancy screening strategies in patients with DM-PM that found that routine use of CT increased the yield rate in detecting occult malignancies from 13% to 28%. A similar strategy has been advocated by Hill et al.8Hill CL Zhang Y Sigurgeirsson B et al.Frequency of specific cancer types in dermatomyositis and polymyositis: a population-based study.Lancet. 2001; 357: 96-100Abstract Full Text Full Text PDF PubMed Scopus (896) Google Scholar Traditionally, if findings on the initial malignancy screening were normal, the patient was considered free of cancer, and searching for occult malignancy with additional investigations was not recommended. Today, some investigators advocate annual reevaluation for underlying malignancy in patients with myositis in whom a malignancy was not found on initial evaluation. The efficacy of this approach was indirectly assessed by a Danish cohort study that found an increased incidence of malignancies in patients with DM-PM in the first 2 years after diagnosis, with a decline in the second year and then no notable increase in subsequent years of follow-up.11Chow WH Gridley G Mellemkjaer L McLaughlin JK Olsen JH Fraumeni Jr, JF Cancer risk following polymyositis and dermatomyositis: a nationwide cohort study in Denmark.Cancer Causes Control. 1995; 6: 9-13Crossref PubMed Scopus (182) Google Scholar Therefore, it may be reasonable to continue annual surveillance for the first 2 to 3 years, then discontinue if there is no sign of relapsing myositis. However, cases of ovarian cancer occurring up to 5 years after the manifestation of DM were reported recently. Consequently, Provost and Flynn12Provost TT Flynn JA Dermatomyositis.in: Provost TT Flynn JA Cutaneous Medicine: Cutaneous Manifestations of Systemic Disease. BC Decker Inc, Hamilton, Ontario2001: 82-103Google Scholar recommend screening women with serum CA 125 measurements twice yearly and performing annual pelvic and transvaginal ultrasonography for up to 5 years. Until clear guidelines for cancer screening in patients with inflammatory myopathies are established, physicians must exercise their best judgment. Which strategy will ultimately prove to be beneficial to the patient and cost-effective remains to be determined.