case 8-2015, a 68-year-old man with multiple myeloma, skin tightness, arthralgias and edema
DESCRIPTION
Dr. Naina Rastalsky (Medicine): A 68-year-old man with multiple myeloma was seenin the rheumatology clinic of this hospital because of increasing skin tightness,joint pain, and swelling of the hands and feet.The patient had been well until 2 years before this presentation, when anemiawas noted on routine examination at another hospital. During the next 7 months,endoscopic and colonoscopic screening examinations were negative. Pathologicalexamination of a bone marrow–biopsy specimen and aspirate revealed 30% plasmacells; flow-cytometric studies revealed an IgG lambda M component. A diagnosisof multiple myeloma was made. Skeletal radiographs reportedly revealed multiplelytic lesions. Lenalidomide, bortezomib, and dexamethasone were administered,followed by cyclophosphamide. Nine months before this presentation, the patientwas admitted to this hospital; melphalan hydrochloride was administered, andautologous stem-cell transplantation was performed. Results of follow-up studieswere consistent with complete remission.Three months before this presentation, the patient was seen by an orthopedistat this hospital for evaluation of low-back pain of 1 year’s duration. Magnetic resonanceimaging (MRI) of the lumbar spine, performed after the administration ofintravenous gadolinium, revealed multilevel degenerative changes, multiple enhancinglesions in the lumbar spine and left iliac bone, and compression fractures of thefirst and second lumbar vertebrae, findings consistent with the history of multiplemyeloma.TRANSCRIPT
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Pr esen tation of C a se
Dr. Naina Rastalsky (Medicine): A 68-year-old man with multiple myeloma was seen in the rheumatology clinic of this hospital because of increasing skin tightness, joint pain, and swelling of the hands and feet.
The patient had been well until 2 years before this presentation, when anemia was noted on routine examination at another hospital. During the next 7 months, endoscopic and colonoscopic screening examinations were negative. Pathological examination of a bone marrowbiopsy specimen and aspirate revealed 30% plasma cells; flow-cytometric studies revealed an IgG lambda M component. A diagnosis of multiple myeloma was made. Skeletal radiographs reportedly revealed multiple lytic lesions. Lenalidomide, bortezomib, and dexamethasone were administered, followed by cyclophosphamide. Nine months before this presentation, the patient was admitted to this hospital; melphalan hydrochloride was administered, and autologous stem-cell transplantation was performed. Results of follow-up studies were consistent with complete remission.
Three months before this presentation, the patient was seen by an orthopedist at this hospital for evaluation of low-back pain of 1 years duration. Magnetic reso-nance imaging (MRI) of the lumbar spine, performed after the administration of intravenous gadolinium, revealed multilevel degenerative changes, multiple enhanc-ing lesions in the lumbar spine and left iliac bone, and compression fractures of the first and second lumbar vertebrae, findings consistent with the history of multiple myeloma.
Two months before this presentation, swelling and pain in the hands occurred, followed by pedal edema, tightening of the skin of the hands and feet, and diffuse hyperpigmentation on the trunk, arms, and legs. Maintenance therapy with lenalido-mide was begun, but it was stopped during the first cycle because of worsening symptoms.
Diffuse joint pain occurred and hyperpigmentation increased. One month before this presentation, on evaluation in the outpatient cancer center of this hospital,
From the Department of Medicine, Johns Hopkins Hospital, and the Department of Medicine, Johns Hopkins University School of Medicine both in Baltimore (F.W.); and the Departments of Medicine (R.P.F.), Radiology (J.-A.O.S.), and Pa-thology (R.M.N.), Massachusetts Gener-al Hospital, and the Departments of Medicine (R.P.F.), Radiology (J.-A.O.S.), and Pathology (R.M.N.), Harvard Medi-cal School both in Boston.
N Engl J Med 2015;372:1056-67.DOI: 10.1056/NEJMcpc1409840Copyright 2015 Massachusetts Medical Society.
Founded by Richard C. Cabot Eric S. Rosenberg, M.D., Editor Nancy Lee Harris, M.D., Editor Jo-Anne O. Shepard, M.D., Associate Editor Alice M. Cort, M.D., Associate Editor Sally H. Ebeling, Assistant Editor Emily K. McDonald, Assistant Editor
Case 8-2015: A 68-Year-Old Man with Multiple Myeloma, Skin Tightness,
Arthralgias, and EdemaFredrick Wigley, M.D., Robert P. Friday, M.D., Ph.D., Jo-Anne O. Shepard, M.D.,
and Rosalynn M. Nazarian, M.D.
Case Records of the Massachusetts General Hospital
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the red-cell indexes and results of liver-function tests were normal, as were blood levels of electro-lytes, calcium, phosphorus, magnesium, glucose, thyrotropin, iron, iron-binding capacity, ferritin, and folate; other test results are shown in Table 1. Total urine protein was 90 mg per liter (reference range, 0 to 135). Fine-needle aspiration biopsy of a fat pad was performed, and pathological ex-amination of the specimen revealed no evidence of malignant cells or amyloid. A transthoracic echocardiogram showed trace mitral regurgita-tion, trace tricuspid insufficiency, and a left ven-tricular ejection fraction of 64% and showed that the ascending aorta was 41 mm in diameter (refer-ence diameter,
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T h e n e w e ngl a nd j o u r na l o f m e dic i n eTa
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-
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Case Records of the Massachusetts Gener al Hospital
Var
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stain revealed finely granular mucin deposits inter-spersed between dermal collagen bundles (Fig. 1D). An elastic-tissue stain revealed preservation of
dermal elastic fibers, with straightening and par-allel arrangement (Fig. 1E).
Dr. Rastalsky: Three months after this presen-
Figure 1. Skin-Biopsy Specimen.
Hematoxylin and eosin staining of histologic sections of a skin-biopsy specimen from the dorsum of the left hand revealed a normal epidermis with dermal collagen expansion involving the subcutaneous tissue (Panel A, asterisk); there is adnexal atrophy with periadnexal fat loss (Panel A, arrow). A sparse lymphoplasmacytic infiltrate was identi-fied at the junction of the dermis and the subcutaneous fat (Panel B, arrow). There were areas of reticular dermal fi-broblast hypocellularity (Panel C). An immunohistochemical stain for CD34 shows a diffuse loss of CD34 expression in dermal spindle cells (Panel C, inset). A colloidal iron stain shows interstitial mucin deposits (Panel D). An elastic-tissue stain shows preservation of dermal elastic fibers, with parallel arrangement and straightening (Panel E, arrow).
A B
DC
E
*
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tation, prednisone was administered for persistent stiffness. The patient reported extreme fatigue and increasing dyspnea on exertion during the pre-ceding 3 months. Results of tests performed at the other hospital are shown in Table 1. Chest imaging was performed because of the worsen-ing shortness of breath.
Dr. Jo-Anne O. Shepard: Computed tomography (CT) of the chest revealed reticulation in the sub-pleural region at the lung bases and bronchiolec-tasis (Fig. 2A). There was no evidence of pulmo-nary edema. These findings were suggestive of nonspecific interstitial pneumonia. Soft-tissue windows showed a small pleural effusion on the right side and minimal dilatation of the main pulmonary artery that could be correlated with pulmonary hypertension (Fig. 2B). The esopha-gus was diffusely dilated and contained contrast material throughout. A representative sagittal image showed generalized osteopenia, multiple lytic lesions throughout the spine and ribs, and multiple healed fractures, including one in the sternum (Fig. 2C). These skeletal findings were consistent with the history of multiple myeloma.
Dr. Rastalsky: The patient was admitted to this hospital 3.5 months after this presentation. On examination, there were bilateral bronchial breath sounds, crackles at the base of the left lung, ex-tensive hardening of the skin from the hands to the elbows and from the toes to above the knees, and deep bronze discoloration on the trunk, arms, and legs. Joint motion was limited by skin thick-ening. Test results are shown in Table 1. An en-doscopic examination was performed.
Dr. Nazarian: During the endoscopy, a gastric-biopsy specimen was obtained from the antrum; examination of the specimen revealed expansion of the lamina propria and prominent fibromus-cular hyperplasia. Other areas showed ectatic mu-cosal capillaries with occasional fibrin thrombi (Fig. 3). This constellation of findings was con-sistent with gastric antral vascular ectasia (which is also referred to as watermelon stomach be-cause the condition is characterized by the parallel arrangement of longitudinal folds containing di-lated vessels that converge at the pylorus, and this arrangement resembles the stripes on a water-melon).
Dr. Rastalsky: IVIG and bortezomib were ad-ministered. The patient was discharged on the fourth day.
Five days later, the patient reported increased
discomfort and inability to bend his joints and was using a wheelchair. Test results are shown in Table 1. During the next 4 days, confusion de-veloped and he had difficulty with word-finding. Oral intake was poor. Four months after this presentation, he was brought to the emergency department of this hospital; on examination, he was alert, oriented to person only, and had dif-ficulty with word-finding and verbal expression. The blood pressure was 98/63 mm Hg, and there was periorbital and facial edema; the remainder of the examination was unchanged. Test results are shown in Table 1. The peripheral-blood smear showed 2 to 4 schistocytes per high-power field. Urinalysis showed 2+ albumin by dipstick, a spe-cific gravity of 1.015, and a pH of 6.0; the urinary sediment was packed with pigmented, coarsely granular casts and had 10 nondysmorphic eryth-rocytes per high-power field and no cellular casts. The ratio of total spot-urine protein to creatinine was 4.0. CT of the head, performed without the administration of contrast material, was negative. The patient was readmitted to this hospital.
A diagnostic test result was received.
Differ en ti a l Di agnosis
Dr. Fredrick Wigley: This patient had multiple my-eloma that appeared to be in remission, exposure to several drugs, bleeding due to gastric antral vascular ectasia, interstitial pulmonary fibrosis with a small pleural effusion, cognitive dysfunc-tion, and acute renal failure with associated throm-botic microangiopathic anemia. Although he had complications involving multiple organ systems, I will focus my differential diagnosis on his rapidly progressive skin thickening with hyper-pigmentation and associated polyarthritis. In par-ticular, the features and distribution of the skin disease and the degree of pigmentation are ma-jor clues in this case.
Multiple Myeloma and Systemic Amyloidosis
Are the features of this patients illness a direct consequence of multiple myeloma? The labora-tory data including the absence of the mono-clonal protein, the serum free light-chain level of less than 1500 mg per liter, and the kappa:lambda ratio of 0.26 to 1.65 strongly suggest that the myeloma was in remission. In addition, skin le-sions associated with plasma-cell infiltration (plas-macytoma) would appear as nodules rather than
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as the diffuse skin involvement that was described in this case. Likewise, evidence of systemic amy-loidosis was not seen on fat-pad biopsy, echocar-diography, or skin biopsy. Patients with amyloi-dosis usually have hemorrhagic lesions due to the fragility of infiltrated cutaneous vessels, and the joint disease is not very inflammatory and usu-
ally involves proximal joints; the skin and joint disease seen in this case were not consistent with amyloidosis.
Toxic Effects
Is this patients disease a consequence of toxic effects associated with medications or with the recent MRI examination? During the course of this patients treatment, he received several drugs that may have caused a secondary process. Le-nalidomide can cause a diffuse rash, but the rash is usually an eczematous eruption without clini-cally significant skin thickening. Cyclophospha-mide or melphalan hydrochloride can induce a second cancer, and thus it is possible that a para-neoplastic process such as the palmar fasciitis and polyarthritis syndrome could explain some of the features in this case. IVIG can cause renal toxic effects that could in part account for the acute renal failure.
Could this patients rapidly progressive skin thickening and hyperpigmentation be caused by exposure to gadolinium? In rare cases, exposure to gadolinium during an MRI examination can result in nephrogenic systemic fibrosis, a fibrotic process that mainly affects the skin but also af-fects internal organs; lung fibrosis, heart infiltra-tion, and neuropathy have been reported.1 Neph-rogenic systemic fibrosis typically occurs in patients with severe impairment of renal function (with a glomerular filtration rate of
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the arms and trunk, and spare the face. Severe flexion contractures of joints result from fibrosis of deep soft tissue. Dermal fibrosis and intersti-tial mucin deposition with little or no inflam-matory infiltrate are seen on biopsy. This patient may have an increased risk of gadolinium-induced renal disease because of his older age and history of myeloma; however, he had relatively normal results of renal-function tests at the time of the imaging study, and furthermore, his inflamma-tory joint disease was not consistent with neph-rogenic systemic fibrosis.
Myeloma-Related Skin Disorders
Scleredema is a disorder that is characterized by mucin deposition in the dermis.2 It can be associ-ated with a previous infection, diabetes, or mono-clonal gammopathy of undetermined significance (MGUS); it has also been associated with multi-ple myeloma. Scleredema is characterized by non-pitting doughy or woody induration of skin of the neck, back (especially the middle of the back), and shoulders, with sparing of the distal limbs. The distribution of skin involvement in this pa-tient is not typical of scleredema.
Scleromyxedema is a form of lichen myxede-matosus (papular mucinosis) that is almost always associated with IgG MGUS. Several cases of sclero-myxedema have been associated with multiple myeloma.3 This rare disorder has four diagnostic criteria: a generalized papular and sclerodermoid eruption, a triad of findings on microscopic ex-amination of skin-biopsy specimens (mucin de-position, fibroblast proliferation, and fibrosis), a monoclonal gammopathy, and absence of a thy-roid disorder. Involvement of the skin of the face, including papules on the neck, glabella, and postauricular area, is almost always present; the limbs and back can also be affected. Linear streaks of papules are characteristic of scleromyx-edema, and hyperpigmentation is rare and mild. Unlike patients with nephrogenic systemic fibro-sis, patients with scleromyxedema can have a slight superficial, perivascular, lymphoplasmacytic in-flammatory-cell infiltrate.4 Systemic disease is common and can have neurologic, musculoskele-tal, cardiac, gastrointestinal, pulmonary, and he-matologic manifestations (including myeloma).5,6
Inflammatory polyarthritis may also occur. In addition, acute renal crisis has been reported in patients with scleromyxedema; in such cases, find-ings consistent with thrombotic microangiopathic
anemia, including narrowed glomerular capillar-ies, endothelial proliferation, and microthrombi, are seen.7-9 Many of the features described in this case could be explained by scleromyxedema; how-ever, the absence of skin papules, one of the four diagnostic criteria, makes this diagnosis unlikely.
Eosinophilic fasciitis (Shulmans syndrome) should also be considered because it has been associated with hematologic diseases, including multiple myeloma. In patients with this disorder, there is a rapid onset of skin changes on the arms and legs and sometimes the trunk, with sparing of the face and hands.10 Fibrosis of deep soft tis-sue in the fascia leads to contractures; dimpling of the skin (peau dorange), particularly of the upper inner arms and forearms, is typical. Sys-temic disease is uncommon, but an inflamma-tory rheumatoid-like arthritis can be seen. Eosino-philia is present in approximately 80% of cases, and testing for antinuclear antibodies is negative. The clinical features in this case are not sugges-tive of eosinophilic fasciitis.
Scleroderma
Systemic sclerosis, or scleroderma, is an autoim-mune disease associated with skin fibrosis and multisystem involvement.11 Obliterative vascular disease can lead to scleroderma renal crisis, with manifestations such as thrombotic microangio-
Figure 3. Gastric-Biopsy Specimen (Hematoxylin and Eosin).
Examination of a gastric-biopsy specimen from the antrum reveals expansion of the lamina propria and prominent fibromuscular hyperplasia. There were ec-tatic mucosal capillaries with occasional fibrin throm-bi (inset). This constellation of findings is consistent with gastric antral vascular ectasia (watermelon stomach).
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pathic anemia, pulmonary hypertension, cardiac disease, and gastrointestinal bleeding due to gas-tric antral vascular ectasia; all these features were seen in this case. Interstitial lung disease is com-mon in patients with scleroderma, particularly in those with antibodies to Scl-70 (topoisomerase I). There is an increased risk of cancer among patients with scleroderma.12 Skin disease associ-ated with scleroderma has a highly variable course, but a subset of patients present with rapidly ad-vancing, widespread disease that usually affects the distal limbs first, spreads proximally to the trunk and face, and spares the back. Scleroder-ma begins as an inflammatory process that is commonly characterized by pitting edema and then transforms into a fibrotic skin disease that is often associated with intense hyperpigmenta-tion, inflammatory joint disease, and eventually, joint contractures. Examination of skin-biopsy specimens often reveals dermal fibrosis with dense extracellular matrix, a mild perivascular inflam-matory infiltrate, and no excess mucin. This patient had many features of scleroderma; however, the mucin deposition that was seen on histopathologic examination would be atypical of this diagnosis.
Summary
I think the differential diagnosis narrows to two similar but discrete clinical syndromes: sclero-derma and scleromyxedema (Table 2). The find-ing of mucin deposition on examination of the skin-biopsy specimen argues against a diagnosis of scleroderma. However, I think scleroderma is likely, given the overall clinical features (including interstitial lung disease, bleeding due to gastric antral vascular ectasia, inflammatory joint disease with limitations of motion, and rapidly emerging diffuse, hyperpigmented, fibrotic skin disease without papules). The event that led to his last presentation to the hospital was probably sclero-derma renal crisis. Normotensive scleroderma re-nal crisis has been reported, but this patient was probably dehydrated, and cardiac dysfunction could have accounted in part for his hypoten-sion. A subset of patients with scleroderma and anti-RNA polymerase III antibodies present with rapid diffuse skin disease, fibrosis of deep soft tissue, friction rubs, and joint contractures. They are unlikely to have clinically significant intersti-tial lung disease but are at high risk for sclero-derma renal crisis (20%).22 They often have pri-
mary scleroderma-related heart disease and are at increased risk for concomitant cancer and scleroderma.23
I suspect that a diagnostic test for the detec-tion of anti-RNA polymerase III antibodies was performed in this case; a positive test would con-firm the clinical diagnosis of scleroderma. It is possible that examination of a tissue-biopsy spec-imen revealed the presence of gadolinium, the cause of nephrogenic systemic fibrosis, but this is doubtful. I considered thrombotic thrombocy-topenic purpura as an explanation of the patients central nervous system and renal disease, but this diagnosis would not explain the previous find-ings of the skin, joints, and other organ systems. In making a diagnosis of scleromyxedema, it would be necessary to perform a kidney biopsy to look for mucin deposition in renal vessels. My diagnosis in this patient with multiple myeloma that has been previously treated and is in remis-sion is scleroderma.
Dr. Eric S. Rosenberg (Pathology): Dr. Friday, what was your impression when you evaluated this patient?
Dr. Robert P. Friday: The patient had a history of multiple myeloma and had multisystem disease with prominent and rapidly progressive skin fibro-sis, and these factors guided the initial decision to administer IVIG for suspected scleromyxedema. However, there were a number of competing di-agnostic considerations. The detection of intersti-tial fibrosis on lung imaging in a patient with progressive dyspnea and bleeding due to gastric antral vascular ectasia increased our suspicion for scleroderma. At the time of admission, the findings in the urinary sediment and the relative hypotension in the presence of altered mental status and acute kidney injury supported a diag-nosis of acute tubular necrosis, but the presence of schistocytes and thrombocytopenia on the peripheral-blood smear raised concerns about scleroderma renal crisis. The patient had also received prednisone, and the administration of prednisone is a known risk factor for scleroder-ma renal crisis, including normotensive scleroder-ma renal crisis.24
Clinic a l Di agnosis
Diffuse systemic sclerosis (scleroderma), with scleroderma renal crisis.
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Dr . Fr edr ick W igle y s Di agnosis
Systemic sclerosis (scleroderma) in a patient with multiple myeloma that has been treated and is in remission.
Pathol o gic a l Discussion
Dr. Nazarian: Fibrosing dermopathies are a group of diseases with overlapping clinicopathological features.10,13-15,25-27 Assessment of subcutaneous involvement and dermal fibroblast cellularity on routine histologic examination can help to dif-ferentiate among these conditions. Useful ancil-lary studies (which were performed in this case) include colloidal iron staining to assess for mu-cin deposition, elastic-tissue staining to assess
the quality and quantity of elastic fibers, and immunohistochemical staining to assess for CD34 expression in dermal spindle cells.16,17
In this case, serologic studies were remarkable for the presence of a high titer of antinuclear antibodies (1:1280), a positive titer of anti-RNA polymerase III antibodies (>80; normal titer,
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T h e n e w e ngl a nd j o u r na l o f m e dic i n e
Raynauds phenomenon or nailfold capillary ab-normalities, led to some diagnostic confusion and underscored the multidisciplinary diagnos-tic challenge in this case. Ultimately, correlation of the histopathological features with clinical his-tory and laboratory findings established the fi-nal anatomical diagnosis of scleroderma.
Discussion of M a nagemen t a nd Foll ow-up
Dr. Rosenberg: Dr. Friday, would you tell us what happened with this patient?
Dr. Friday: The patient was initially treated with intravenous fluids. Renal biopsy was con-sidered, but it was decided that the results would probably not influence therapy and the proce-dure would expose this critically ill patient to unnecessary risk. Hemodialysis was initiated, and low doses of enalapril were administered. The patients mental status improved dramatically with hemodialysis, but over a period of several days there was no meaningful recovery of renal function. Despite having clearer mentation, the patient had severe swallowing difficulties; on video fluoroscopic evaluation, marked pharyngeal dys-function was present, and thus a gastric tube was placed. He was transferred to a rehabilitation fa-cility for further care. Four days after discharge,
the patient was found unresponsive and pulseless. No resuscitation efforts were pursued, in accor-dance with the patients wishes.
Dr. John H. Stone (Medicine): Why did pharyn-geal dysfunction develop very late in the course of this patients disease?
Dr. Wigley: Swallowing difficulties can be seen in a subset of patients with scleroderma with very rapid, diffuse involvement of the head, neck, and face. There are two problems: one is difficulty with initiation of swallowing, and the other is dyspha-gia due to esophageal dysfunction. Patients who have trouble with initiation of swallowing have pharyngeal involvement due to either inflamma-tory myositis or fibrosis of soft tissue.
Fina l Di agnosis
Scleroderma.This case was presented at the Medical Case Conference.Dr. Wigley reports receiving consulting fees from Eiger Bio-
pharmaceuticals and grant support from Actelion Pharmaceuti-cals, MedImmune, Novartis, United Therapeutics, CSL Behring, Sanofi Aventis, and HoffmannLa Roche; and Dr. Shepard, re-ceiving consulting fees for providing expert testimony in a legal case regarding thoracic imaging. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
We thank Dr. John H. Stone for his help in organizing this conference and with the preparation and editing of the case history.
References1. Piera-Velzquez S, Sandorfi N, Jim-nez SA. Nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy: clini-cal aspects. Skinmed 2007; 6: 24-7.2. Yaqub A, Chung L, Rieger KE, Fioren-tino DF. Localized cutaneous fibrosing disorders. Rheum Dis Clin North Am 2013; 39: 347-64.3. Muldrow ML, Bailin PL. Scleromyx-edema associated with IgG lambda multi-ple myeloma. Cleve Clin Q 1983; 50: 189-95.4. Rongioletti F, Rebora A. Updated classification of papular mucinosis, li-chen myxedematosus, and scleromyxede-ma. J Am Acad Dermatol 2001; 44: 273-81.5. Rongioletti F, Merlo G, Cinotti E, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients. J Am Acad Dermatol 2013; 69: 66-72.6. Blum M, Wigley FM, Hummers LK. Scleromyxedema: a case series highlight-ing long-term outcomes of treatment with intravenous immunoglobulin (IVIG). Medicine (Baltimore) 2008; 87: 10-20.7. Kantor GR, Bergfeld WF, Katzin WE, et al. Scleromyxedema associated with
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13. Kucher C, Xu X, Pasha T, Elenitsas R. Histopathologic comparison of nephro-genic fibrosing dermopathy and sclero-myxedema. J Cutan Pathol 2005; 32: 484-90.14. Nashel J, Steen V. Scleroderma mim-ics. Curr Rheumatol Rep 2012; 14: 39-46.15. Rongioletti F, Patterson JW, Rebora A. The histological and pathogenetic spec-trum of cutaneous disease in monoclonal gammopathies. J Cutan Pathol 2008; 35: 705-21.16. Walters R, Pulitzer M, Kamino H. Elastic fiber pattern in scleroderma/mor-phea. J Cutan Pathol 2009; 36: 952-7.17. Aiba S, Tabata N, Ohtani H, Tagami H. CD34+ spindle-shaped cells selectively disappear from the skin lesion of sclero-derma. Arch Dermatol 1994; 130: 593-7.18. Khandpur S, Singh S, Sharma VK, Gupta R, Singh MK. Linear morphea with secondary mucinosis. Indian J Dermatol Venereol Leprol 2009; 75: 388-90.19. Stone JH, ed. A clinicians pearls and myths in rheumatology. London: Spring-er, 2010.20. Steen VD. Autoantibodies in systemic
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sclerosis. Semin Arthritis Rheum 2005; 35: 35-42.21. Chung L, Utz PJ. Antibodies in sclero-derma: direct pathogenicity and pheno-typic associations. Curr Rheumatol Rep 2004; 6: 156-63.22. Nikpour M, Hissaria P, Byron J, et al. Prevalence, correlates and clinical useful-ness of antibodies to RNA polymerase III in systemic sclerosis: a cross-sectional analysis of data from an Australian co-hort. Arthritis Res Ther 2011; 13: R211.
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