Fasciitis as a common lesion of dermatomyositis demonstrated early after disease onset by en bloc biopsy combined with magnetic resonance imaging.код для вставкиСкачать
ARTHRITIS & RHEUMATISM Vol. 62, No. 12, December 2010, pp 3751–3759 DOI 10.1002/art.27704 © 2010, American College of Rheumatology Fasciitis as a Common Lesion of Dermatomyositis, Demonstrated Early After Disease Onset by En Bloc Biopsy Combined With Magnetic Resonance Imaging Ken Yoshida,1 Daitaro Kurosaka,1 Kensuke Joh,2 Satoshi Matsushima,1 Eigo Takahashi,1 Kenichiro Hirai,1 Kentaro Noda,1 Taro Ukichi,1 Kazuhiro Furuya,1 Maimi Yanagimachi,1 Isamu Kingetsu,1 Kunihiko Fukuda,1 and Akio Yamada1 Conclusion. Fasciitis was histopathologically demonstrated in patients with newly diagnosed adultonset DM as early as 2 months after the onset of muscle symptoms. These results indicate that fasciitis is a common lesion of DM and suggest that the fascial microvasculature is the primary site of inflammatory cell infiltration in DM. Fasciitis may contribute to muscle symptoms in patients with DM without myositis. Objective. To investigate whether fasciitis is histopathologically demonstrable in patients with dermatomyositis (DM), and to analyze the process of inflammatory progression in myopathy accompanying DM. Methods. STIR or fat-suppressed T2-weighted magnetic resonance imaging (MRI) and en bloc biopsy were performed in 14 patients with newly diagnosed adult-onset DM. The severity of inflammatory cell infiltration around the fascial and intramuscular small blood vessels was evaluated using the total vascular inflammation score (TVIS). Results. In all patients, MRI revealed abnormal hyperintensity in the fascia and in marginal sites of the muscle, predominantly over central sites. En bloc biopsy revealed the presence of fasciitis in most of the patients, as shown by inflammatory infiltrates around the fascial small blood vessels. In those patients who underwent en bloc biopsy earlier than 2 months after the appearance of muscle symptoms, the TVIS of the fascia was significantly higher than the TVIS of the muscle. In contrast, in those patients who underwent en bloc biopsy >2 months after muscle symptom onset, the TVIS of the fascia did not differ significantly from the TVIS of the muscle. Dermatomyositis (DM) is a disorder characterized by inflammation of the muscle and typical cutaneous findings (1). It has been reported that the intramuscular microvasculature is the primary target in DM (2–4). Microvascular deposition of immunoglobulin, complement, and membrane attack complex was hypothesized as one of the mechanisms of vessel injury (5,6). The complement deposits induce endothelial cell edema, vacuolization, capillary necrosis, and perivascular inflammation (7). Histopathologically, inflammatory infiltrates are predominantly perivascular or clustered in the interfascicular septa and around, rather than within, the fascicles (8). However, in some patients, no inflammatory cells are evident on muscle biopsy (9–11). Even when the muscle biopsy is performed at the site of myalgia, the biopsy will often fail to reveal inflammatory infiltrates in the muscle or structural changes in the muscle fibers. It remains unclear why muscle symptoms (i.e., myalgia and weakness) occur even in the absence of inflammatory cells in the muscle or structural changes in the muscle fibers, and it remains to be elucidated what other factors might cause the muscle symptoms. Kimball et al reported that edema in the skin, subcutaneous tissue, and fascia, as revealed by STIR magnetic resonance imaging (MRI), is common in patients with juvenile DM and is often undetected by 1 Ken Yoshida, MD, PhD, Daitaro Kurosaka, MD, PhD, Satoshi Matsushima, MD, PhD, Eigo Takahashi, MD, Kenichiro Hirai, MD, Kentaro Noda, MD, Taro Ukichi, MD, Kazuhiro Furuya, MD, Maimi Yanagimachi, MD, Isamu Kingetsu, MD, PhD, Kunihiko Fukuda, MD, PhD, Akio Yamada, MD: Jikei University School of Medicine, Tokyo, Japan; 2Kensuke Joh, MD, PhD: Sendai Shakai Hoken Hospital, Miyagi, Japan. Address correspondence and reprint requests to Ken Yoshida, MD, PhD, Division of Rheumatology, Department of Internal Medicine, Jikei University School of Medicine, 3-25-8, Nishi-shinbashi, Minato-ku, Tokyo 105-8461, Japan. E-mail: email@example.com. Submitted for publication December 8, 2009; accepted in revised form August 5, 2010. 3751 3752 YOSHIDA ET AL Table 1. Characteristics of the patients with newly diagnosed adult-onset dermatomyositis* Patient/age/sex Maximum CK, IU/liter Jo-1 ILD Cancer Pretreatment Biopsy site Treatment after en bloc biopsy 1/64/F 2/34/F 3/40/M 4/38/M 5/58/M 6/53/M 7/51/M 8/30/F 9/73/M 10/63/M 11/56/F 12/54/F 13/32/M 14/51/F 249 480 176 363 229 2,833 77 6,530 895 1,342 246 35 2,428 82 – – – – – ⫹ – – – – – – ⫹ – – ⫹ ⫹ – ⫹ ⫹ – – – – – ⫹ ⫹ – SCLC – – – – – – – – LC BC – – – – – – – – – – – – – – Pred. 5 mg – Pred. 10 mg Sartorius Deltoid Deltoid Rectus femoris Biceps brachii Biceps brachii Biceps brachii Biceps brachii Biceps brachii Deltoid Biceps brachii Deltoid Biceps brachii Sartorius Cisplatin, etoposide, radiation Pred. 50 mg, CSA 150 mg Pred. 60 mg, CSA 200 mg Pred. 50 mg, CSA 200 mg, MTX Pred. 60 mg, tacrolimus 3 mg Pred. 60 mg, tacrolimus 3 mg Pred. 60 mg Pulse MP, pred. 60 mg, MTX Pred. 50 mg Pred. 60 mg Pred. 60 mg Pred. 60 mg, tacrolimus 5 mg Pred. 60 mg, CSA 200 mg Pred. 60 mg * CK ⫽ creatine kinase; ILD ⫽ interstitial lung disease; SCLC ⫽ small cell lung carcinoma; pred. ⫽ prednisolone; CSA ⫽ cyclosporin A; MTX ⫽ methotrexate; MP ⫽ methylprednisolone; LC ⫽ lung cancer; BC ⫽ breast cancer. routine clinical and laboratory evaluations (12). Although evidence of edema on STIR MRI is generally correlated with the presence of tissue inflammation or edema (13,14), it is unknown whether, in DM, MRI evidence of fascial edema is indicative of the histopathologic feature of fasciitis or edema. Interestingly, there have been 2 case reports describing a patient with adult-onset amyopathic DM whose disease was accompanied by fasciitis, as revealed by histopathologic assessment and by the detection of inflammatory infiltrates not in the muscle, but in the fascia (15,16). Allen et al speculated that fasciitis may represent an early lesion in the evolution of DM (15). In DM, histopathologic changes in the muscle have previously been investigated in detail. However, changes in the fascia remain largely unknown, because histopathologic evaluation of the fascia has been reported to have been performed in only 2 patients with DM. MRI is useful not only to define structural aberrations of the muscle and to assess disease activity, but also to guide muscle biopsy and minimize sampling errors (17–19). In the present study, we examined whether fasciitis is histopathologically demonstrable after the onset of muscle symptoms in DM, and analyzed the process of inflammatory progression. To this end, we performed proximal muscle MRI in combination with en bloc muscle biopsy, the latter involving resection of the skin, subcutaneous tissue, fascia, and muscle, which differs from general biopsy, in which only the muscle, but not the fascia, is resected. PATIENTS AND METHODS Patients. Nineteen patients who were newly diagnosed as having definite or probable adult-onset DM, in accordance with the Bohan and Peter criteria (1), between June 2006 and May 2010 were identified at the Division of Rheumatology of Jikei University Hospital in Tokyo, Japan. Of 19 patients, 14 underwent en bloc biopsy and these patients were enrolled in the study. The study protocol was approved by the ethics committee of Jikei University School of Medicine, and informed consent was obtained from all patients. The patients had not been treated with prednisolone for DM or had been treated with ⱕ10 mg/day prednisolone for other diseases. We excluded patients who had been receiving immunosuppressive agents or ⬎10 mg/day prednisolone and those who had already undergone general biopsy. The median age at diagnosis was 49.79 years (range 30–73 years), and there were 6 women and 8 men. Eleven patients were diagnosed as having definite DM and 3 patients as having probable DM. Gottron’s papules were observed in all patients and a heliotrope rash was observed in 11 patients. Positive findings on electromyography were obtained in 8 patients. Three patients (patients 7, 11, and 13 in Table 1) had clinically amyopathic DM, diagnosed in accordance with previously proposed features of either amyopathic DM or hypomyopathic DM (20), and their muscle symptoms were very mild at the time of en bloc biopsy. Levels of serum creatine kinase (normal range 25–160 IU/liter) varied from normal to increased values (range 35–6,530 IU/liter). Anti–Jo-1 antibody positivity was observed in 2 patients. Six patients had interstitial lung disease (ILD), and 3 patients without ILD had previously had malignant neoplasms. The shortest period from muscle symptom appearance to en bloc biopsy at the site was 1 week, and the longest period was 12 months. The site of en bloc biopsy was the deltoid or biceps brachii muscle in the brachium, and the rectus femoris or sartorius muscle in the thigh (Table 1). En bloc biopsy was also performed on 6 patients with other rheumatic diseases in whom polymyositis (PM), DM, or fasciitis was clinically suspected before biopsy. Three patients had PM, 1 had undifferentiated myopathy, 1 had polyarteritis nodosa (PAN) in muscles of the lower extremities, and 1 had polymyalgia rheumatica (PMR). These subjects constituted a comparison group. FASCIITIS AS A COMMON LESION OF DERMATOMYOSITIS En bloc biopsy combined with MRI. Before en bloc biopsy, muscle MRI of the thighs and/or brachia was performed on all patients. En bloc biopsy was carried out on the site at which patients were conscious of even mild muscle pain or weakness and in which STIR or fat-suppressed T2-weighted MRI had revealed an abnormal hyperintense area. Furthermore, we confirmed the enhancement in the same site on gadolinium-enhanced fat-suppressed T1-weighted images. En bloc biopsy, which involved resection of the skin, subcutaneous tissue, fascia, and muscle, was performed using an open biopsy technique, with the patient under local anesthesia. All biopsy samples were fixed in 10% neutral-buffered formalin and embedded in paraffin. For each biopsy sample obtained, 3-m–thick paraffin-embedded sections were prepared and mounted on glass slides. These sections were stained with hematoxylin and eosin, Masson’s trichrome, or elastic–van Gieson stain. Histopathology. All en bloc biopsy specimens were assessed for histopathologic changes by an experienced pathologist (KJ) who was blinded to the patients’ medical history. The intramuscular small blood vessels were defined as a small artery, arteriole, blood capillary, venule, and small vein in the interfascicular septum and in the fascicle. The fascial small blood vessels were the same as those in the fascia, including those in the epifascial tissue and subfascial tissue. The grade and distribution of perivascular inflammatory changes in the fascia and muscle were evaluated using a modification of the semiquantitative scoring system for focal lymphocytic sialadenitis, with assessment of features according to the international classification criteria for Sjögren’s syndrome (21). Briefly, the vascular inflammation score (VIS) was defined as the number of aggregates of ⱖ50 inflammatory cells infiltrating around a small blood vessel or a group of small vessels per 4-mm2 area of tissue. The upper limit of the VIS in the 4-mm2 area was not set. The total vascular inflammation score (TVIS) was defined as the summation of the VIS in the 3 fields that showed the most remarkable perivascular infiltrates. Fasciitis was defined as a TVIS of ⱖ3 in the fascia, to exclude very mild inflammation. The TVIS was assessed by a pathologist and a rheumatologist (KJ and KY, respectively), both of whom were blinded to the clinical data. In those cases in which the difference between the 2 measurements from the 2 observers was ⱖ3, the appropriateness of the selection of 4-mm2 areas was mutually validated by the 2 observers, and the TVIS was re-reviewed in those areas showing more remarkable perivascular infiltrates until the observers reached a consensus. In other cases, the mean values from 2 measurements were used for statistical analysis. Immunohistochemical staining. Immunohistochemistry was performed on paraffin-embedded sections using Dako ChemMate EnVision, according to the manufacturer’s instructions. The primary antibodies were as follows: anti-human CD3 (clone PS1, diluted 1:1; Nichirei), anti-human CD4 (clone IF6, diluted 1:1; Nichirei), anti-human CD8 (clone C8/144B, diluted 1:1; Nichirei), anti-human CD20 (clone L26, diluted 1:500; Dako), anti-human CD79␣ (clone JCB117, diluted 1:200; Dako), and anti-human CD68 (clone KP1, diluted 1:100; Dako). The chromogen was 3,3⬘-diaminobenzidine tetrahydrochloride and the sections were counterstained with hematoxylin. An isotype-matched irrelevant antibody was included as a negative control for all staining. The first and last sections of 3753 each series of consecutive sections were stained with hematoxylin and eosin to confirm that the histopathologic structure remained unchanged across the consecutive sections. For each sample, we performed qualitative analysis on the number of CD20⫹ B cells and CD79␣⫹ B or plasma cells (⫺ ⫽ no positive cells, ⫹/⫺ ⫽ a few positive cells, and ⫹ ⫽ significant infiltration of positive cells). The CD4:CD8 cell ratio was graded as ⬎1, 1, or ⬍1. Statistical analysis. Differences in the TVIS between experimental groups were analyzed by the nonparametric Mann-Whitney U test using GraphPad Prism software, version 4.0. P values less than 0.05 were considered statistically significant. RESULTS MRI findings. STIR or fat-suppressed T2weighted MRI was performed before en bloc biopsy. In all of the patients with DM, MRI revealed abnormal hyperintense areas in the fascias and muscles, and in 10 patients, this abnormality was also observed in the subcutaneous tissue of the extremities. In patients who underwent en bloc biopsy earlier than 2 months after the appearance of muscle symptoms (patients 1–7, comprising the early-biopsy group), MRI revealed abnormal hyperintense areas that were more predominant in the fascias as compared with the muscles (Figure 1A). In patients who underwent en bloc biopsy ⱖ2 months after the onset of muscle symptoms (patients 8–14, comprising the late-biopsy group), MRI revealed abnormal hyperintense areas that were distributed in equal proportions in the fascias and muscles. In the abnormal hyperintense areas of the fascia, the signal strengths on MRI were approximately equal between patients in the early-biopsy group and those in the late-biopsy group. In the abnormal hyperintense areas of the muscle, the signal strengths were higher in the late-biopsy group than in the early-biopsy group. Moreover, in the late-biopsy group, the signal strength was high at marginal sites of the muscle, predominantly over central sites (Figures 1B, D, and F). In patient 14, for whom the period from the appearance of muscle symptoms to en bloc biopsy at the site was the longest, the abnormal hyperintense areas tended to be diffusely distributed in the muscles, rather than distributed predominantly in marginal sites of the muscles. MRI was sequentially performed twice before treatment in 2 patients with DM (patients 7 and 11). In patient 7, the rash preceded the onset of very mild muscular symptoms. The first MRI revealed no abnormal hyperintense areas, whereas the second MRI, conducted 2 months later, revealed abnormal hyperintense areas in the fascias surrounding the right vastus lateralis, 3754 YOSHIDA ET AL Figure 1. STIR or fat-suppressed T2-weighted magnetic resonance imaging (MRI) of transaxial sections of proximal muscle tissue of the extremities in patients with newly diagnosed adult-onset dermatomyositis. A and B, Areas of high signal intensity (arrowheads) observed in the fascias surrounding the bilateral semimembranosus, semitendinosus, and right vastus lateralis muscles in patient 4 (A), and predominantly in the marginal sites of the bilateral rectus femoris, vastus lateralis, vastus intermedius, and left semitendinosus muscles in patient 8 (B). C–F, Areas of high signal intensity (arrowheads) on consecutive MRI of muscle tissue in patient 11. On the first MRI, hyperintense areas were observed in the fascias surrounding the right deltoid, triceps brachii, and coracobrachialis muscles and the marginal sites of these muscles (C) and in the fascias surrounding the bilateral vastus lateralis muscles (E). On the second MRI, performed 2 months later, the areas of high signal intensity observed in C had progressed from the fascias and marginal sites of the muscles to central sites (D), and those observed in E had progressed from the fascias to marginal sites of the muscles (F). rectus femoris, and left sartorius muscles. In patient 11, slight muscular symptoms occurred after the rash. The first MRI showed abnormal hyperintense areas in the fascias surrounding the right deltoid, triceps brachii, coracobrachialis, and bilateral vastus lateralis muscles (Figures 1C and E), and the second MRI performed 2 months later showed abnormal hyperintense areas in those same fascias and muscles (Figures 1D and F). In the patient with PMR, MRI revealed local hyperintense areas in the fascia and muscle, but extensive areas of hyperintense signal, similar to those detected in patients with DM, were not detected. In the 3 patients with PM and the patient with PAN, significant hyperintense areas were detected in the muscles, but no significant hyperintense areas were revealed in the fascias. In the patient with undifferentiated myopathy, it was difficult to evaluate inflammatory edema on muscle MRI, because marked edema due to hypoalbuminemia was present. Histopathologic findings. En bloc biopsy showed inflammatory infiltrates around the fascial small blood vessels in all 14 patients with DM, and significant fasciitis, defined as a TVIS of ⱖ3 in the fascia, was histopathologically identified in biopsy samples from 12 patients (Figures 2A–D). In the muscle tissue, inflammatory infiltrates around the small blood vessels were observed in 10 patients (Table 2 and Figure 2E), whereas this was not detected in the muscle tissue from 4 patients (patients 2, 4, 5, and 7). All 4 of these latter patients belonged to the early-biopsy group (Table 2). Aggregates of inflammatory cells were observed around the subfascial small blood vessels outside of the tendon, at the muscle–tendon junction, in 4 patients (patients 7, 8, 11, and 13) (representative findings in patient 7 in Figure 2C). In all biopsy specimens from the patients with DM, staining with elastic–van Gieson stain revealed that the small blood vessels containing perivascular inflammatory infiltrates were not arteries, but rather were blood capillaries, venules, and small veins (Figure 2D). Capillaritis and phlebitis were detected, but typical arteritis with fibrinoid necrosis was not detected in any specimen. Eight specimens displayed perifascicular atrophy (Table 2). Structural changes in the muscle fibers (atrophy, degeneration, regeneration, and central nuclei) tended to be correlated with the period from the time of muscle symptom appearance to en bloc biopsy at the site (results not shown). Two specimens (from patients 4 and 7, both in the early-biopsy group) showed structural changes in the muscle fibers, e.g., perifascicular atrophy, even in the absence of inflammatory cells around intramuscular small blood vessels. In particular, patient 4 showed marked structural changes (atrophy, degeneration, regeneration, and central nuclei) (Figure 2F). In 1 of the 3 patients with PM, inflammatory cell FASCIITIS AS A COMMON LESION OF DERMATOMYOSITIS 3755 Figure 2. Findings on light microscopic analysis of en bloc biopsy specimens, as revealed by staining with hematoxylin and eosin (H&E), Masson’s trichrome (MT), or elastic–van Gieson (EVG), from patients with newly diagnosed adult-onset dermatomyositis. A, H&E-stained muscle tissue from patient 5 exhibits fasciitis, as shown by mononuclear cell infiltration around the subfascial capillaries and venules (arrowheads). B, In muscle tissue from patient 4, H&E staining reveals mononuclear cell infiltration around a subfascial venule. C and D, In patient 7, MT staining shows that mononuclear cells are clustered around the subfascial capillaries and venules outside the tendon at the muscle–tendon junction (C), while EVG-stained tissue displays no inflammatory infiltrates around a small artery with internal elastic membrane (arrowhead) and shows mononuclear cell infiltration around an epifascial small vein (D). E, H&E-stained muscle tissue from patient 8 reveals mononuclear cell infiltration around the intramuscular capillaries and venules in the interfascicular septa. F, Atrophy, degeneration, regeneration, and central nuclei are evident in the muscle fibers of patient 4, as shown by H&E staining. (Original magnification ⫻ 100 in A; ⫻ 400 in B and D–F; ⫻ 200 in C.) Table 2. Evaluation of the severity of inflammation and immunophenotype of mononuclear cells in the muscle and fascia of 14 patients with newly diagnosed adult-onset dermatomyositis, grouped according to early- and late-biopsy samples* Muscle Group, patient Early biopsy 1 2 3 4 5 6 7 Late biopsy 8 9 10 11 12 13 14 Fascia Period from symptom onset to biopsy TVIS CD4:CD8 CD20 CD79␣ PA TVIS CD4:CD8 CD20 CD79␣ 1 0 1 0 0 3 0 ⬎1 – ⬎1 – – ⬍1 – ⫹/– – – – – ⫹ – NA – – – – ⫹ – – – ⫹ ⫹ – ⫹ ⫹ 7 2 3 11 6 12 7 ⬎1 ⬎1 ⬎1 ⬎1 1 ⬍1 ⬎1 ⫹/– ⫹/– ⫹ ⫹ ⫹ ⫹ ⫹ NA ⫹ ⫹ ⫹ ⫹ ⫹ ⫹ 1 week 3 weeks 3 weeks 4 weeks 5 weeks 6 weeks 7 weeks 7 5 3 6 8 5 5 ⬎1 1 ⬎1 ⬎1 ⬎1 ⬎1 ⬎1 ⫹ ⫹ ⫹/– ⫹ ⫹ ⫹ ⫹/– ⫹ ⫹ ⫹/– ⫹ ⫹ ⫹ ⫹ ⫹ – – – ⫹ ⫹ ⫹ 4 5 3 11 2 6 7 ⬎1 1 1 ⬎1 ⬎1 ⬎1 ⬎1 ⫹ ⫹ ⫹/– ⫹ – ⫹ ⫹/– ⫹ ⫹ ⫹/– ⫹ ⫹ ⫹ ⫹ 2 months 2 months 3 months 3 months 4 months 4 months 12 months * The period from symptom onset to biopsy was defined as the time from muscle symptom appearance to en bloc biopsy at the involved site. Early biopsy was defined as en bloc biopsy performed earlier than 2 months after the appearance of muscle symptoms, while late biopsy was that performed ⱖ2 months after symptom appearance. Fasciitis was defined as a total vascular inflammation score (TVIS) of the fascia of ⱖ3. The ratio of CD4 to CD8 cells was graded as ⬎1, 1, or ⬍1, while the number of CD20⫹ B cells and CD79␣⫹ B or plasma cells was graded as no positive cells (–), a few positive cells (⫹/–), or significant infiltration of positive cells (⫹). PA ⫽ perifascicular atrophy; NA ⫽ not assessed. 3756 infiltration at endomysial sites was severe, whereas it was mild in 2 of the 3 patients with PM and in the patient with undifferentiated myopathy. In the patient with PAN, severe arteritis with fibrinoid necrosis in the muscle was detected. In the patient with PMR, no inflammatory infiltrates were seen in the muscle. Fasciitis was not detected in any of the 6 patients with other rheumatic diseases. Severity of vascular inflammation of the fascia and muscle. In 10 specimens from the patients with DM, the TVIS of the fascia was higher than the TVIS of the muscle, whereas in 2 other specimens, the TVIS of the fascia was lower than the TVIS of the muscle, and in the remaining 2 specimens, the TVIS of the fascia and muscle were equal (Table 2). In the early-biopsy group (patients 1–7), the TVIS of the fascia was significantly higher than the TVIS of the muscle (P ⫽ 0.0012) (Figure YOSHIDA ET AL 3A). In the late-biopsy group (patients 8–14), the TVIS of the fascia and that of the muscle were both high, with no significant difference between these sites (P ⫽ 0.7104) (Figure 3B). In the muscle, the TVIS in the early-biopsy group was significantly lower than the TVIS in the late-biopsy group (P ⫽ 0.0006) (Figure 3C). In the fascia, the TVIS in the early-biopsy group and that in the late-biopsy group were both high, with no significant difference between groups (P ⫽ 0.4557) (Figure 3D). In all 6 patients with other rheumatic diseases, the TVIS of the fascia was 0. The TVIS scores assigned by the 2 different observers were nearly concordant. In 3 cases, the difference between the scores from the 2 observers was ⱖ3. Thus, the TVIS scores in those 3 cases were re-reviewed in more appropriate 4-mm2 areas, and the scores for the re-reviewed areas reached concordance. Immunohistochemical findings. Immunohistochemical analyses showed that in all specimens from the patients with DM, CD4⫹ cells, CD20⫹ B cells, CD79␣⫹ B or plasma cells, and CD3⫹ T cells were mainly present among the inflammatory mononuclear cells around the fascial and intramuscular small blood vessels. CD68⫹ macrophages were scattered among the inflammatory mononuclear cells, but were not clustered. Sheets of macrophages were not observed. The CD4: CD8 cell ratio was ⬎1 in almost all specimens (Table 2 and Figures 4A, B, D, and E). B cells or plasma cells tended to concentrate at sites in which inflammatory mononuclear cells were clustered (Figures 4C and F). DISCUSSION Figure 3. Vascular inflammation in en bloc biopsy specimens from 14 patients with newly diagnosed adult-onset dermatomyositis. The total vascular inflammation score (TVIS) was determined in the muscle and fascia of patients in the early-biopsy group (A), in whom the period from the muscle symptom appearance to en bloc biopsy at the site was ⬍2 months, and in those in the late-biopsy group (B), in whom the period from the muscle symptom appearance to en bloc biopsy at the site was ⱖ2 months. The TVIS was also determined separately in the muscle (C) and in the fascia (D) in the early- and late-biopsy groups. Bars show the mean and SEM. ⴱ ⫽ P ⬍ 0.05. In the present study, we found that fasciitis is a common lesion in adult-onset DM. STIR or fatsuppressed T2-weighted MRI showed abnormal hyperintensity in the fascias in all 14 patients with adult-onset DM. In addition, en bloc biopsy revealed capillaritis and phlebitis in the fascia in all of the patients and significant fasciitis, defined as a TVIS of the fascia ⱖ3, in most of the patients. These results suggest that fascial edema on MRI can be attributed to fasciitis associated with capillaritis and phlebitis. Kimball et al demonstrated that STIR MRI could detect edema in the skin, subcutaneous tissue, and fascia of patients with juvenile DM and that these changes are very common in juvenile DM (12). However, histopathologic evidence of fasciitis has previously been shown in only 2 patients, and both patients had amyopathic DM (15,16). In contrast, we demonstrated that histopathologically evident fasciitis existed not only in amyopathic DM but also in myopathic DM. FASCIITIS AS A COMMON LESION OF DERMATOMYOSITIS 3757 Figure 4. Immunohistochemical staining of en bloc biopsy specimens from patients with newly diagnosed adult-onset dermatomyositis. A–C, Staining revealed CD4⫹ cells (A), CD8⫹ cells (B), and CD20⫹ B cells (C) among mononuclear cells around the intramuscular venule in the interfascicular septa of patient 13. D–F, Staining revealed CD4⫹ cells (D), CD8⫹ cells (E), and CD20⫹ B cells (F) among mononuclear cells clustered around the subfascial small blood vessels outside the tendon at the muscle–tendon junction in patient 7. B and CD4⫹ cells were present mainly among inflammatory mononuclear cells around small blood vessels in both the muscle and the fascia. The CD4:CD8 cell ratio was ⬎1 in almost all specimens. (Original magnification ⫻ 400.) Eosinophilic fasciitis and macrophagic myofasciitis (22) were not considered in our patients, because none of the patients showed infiltration of eosinophils or sheets of large macrophages in the fascia. Our results suggest that fasciitis is one of the causes of the muscle symptoms in DM. We demonstrated that histopathologically evident fasciitis existed even in DM without intramuscular inflammatory infiltrates. In muscle tissue, capillaries are found in reduced numbers in patients with DM without inflammatory infiltrates (23). A loss of functioning capillaries and phenotypic changes in the endothelial cells could result in local tissue hypoxia and metabolic disturbance (24– 27). Although these metabolic alterations could contribute to muscle fatigue (23), fasciitis may also contribute to muscle symptoms such as myalgia, as suggested by the findings in the 4 patients in the early-biopsy group who showed no intramuscular inflammatory infiltrates. Identification of fasciitis may be helpful for diagnosing DM in the absence of intramuscular inflammatory infiltrates. It has been reported that the primary site of inflammatory cell infiltration in DM is the intramuscular microvasculature (2–4). In this regard, we found that the TVIS of the fascia was high, whereas that of the muscle was low in the early-biopsy group. The TVIS in the late-biopsy group was equally high between the muscle and the fascia. MRI also revealed a fascia-predominant distribution of hyperintense areas in the early-biopsy group, in contrast to that in the late-biopsy group, in whom hyperintense areas were equally distributed in the fascia and muscle. These findings suggest that the fascial microvasculature is the primary target tissue of inflammatory cell infiltration in DM. The degree of intramuscular inflammation differed significantly between the early- and late-biopsy groups. The TVIS of the muscle was higher in the late-biopsy group than in the early-biopsy group, and TVIS of the fascia was comparably high in the 2 groups. The MRI signal of the hyperintense areas in the muscle was stronger in the late-biopsy group than in the earlybiopsy group, and that for the fascia was comparable between the 2 groups. Thus, we can speculate that inflammatory cell infiltration around the small blood vessels occurs originally in the fascia and expands into the muscle along the fascia and interfascicular septum. Alternatively, the 2 groups may represent different types 3758 of DM, such as a fasciitis-dominant type and a mixed type, in which, for the latter type, the extent of inflammation in the fascia and muscle is equal. A myositisdominant type may also exist, since inflammatory infiltrates in tissue specimens from patients 8 and 12 were predominantly localized around the intramuscular microvasculature rather than the fascial microvasculature. Furthermore, intriguing findings were obtained from the MR images from 2 patients (patients 7 and 11), in whom MRI of the extremities was performed twice before treatment for DM. In patient 7, the first MRI revealed no abnormal hyperintense area, but the second MRI performed 2 months later showed abnormal hyperintense areas not in the muscles, but in the fascias. In patient 11, abnormal hyperintense areas were detected on the first MRI in the fascias, and on the second MRI performed 2 months later, the hyperintense areas had progressed from the fascias to marginal sites of the muscles. These MRI findings suggest that inflammation in myopathy progresses from the fascia to the muscle. Immunohistochemistry revealed that in almost all specimens from the patients with DM, B and CD4⫹ cells were present mainly among the inflammatory mononuclear cells around both the fascial and intramuscular small blood vessels. In the muscle, the infiltrates contain high percentages of B and CD4⫹ T cells, and the proportion of B and CD4⫹ T cells is highest at perivascular sites and lowest at endomysial sites (28,29). Greenberg et al recently reported that the majority of CD4⫹ cells in muscle biopsy samples from patients with DM are not helper T cells but plasmacytoid dendritic cells (PDCs) (30). Although the CD4⫹ cells detected in our study may also have included PDCs, the CD4:CD8 cell ratio in the fascia was similar to that in the muscle. These results indicate that capillaritis and phlebitis present in the fascia are not caused by complications from other diseases such as systemic vasculitis, according to the definition and classification of vasculitis adopted at the Chapel Hill Consensus Conference (31), but rather can be attributed to DM, and this is also true for capillaritis and phlebitis found in the muscle. In the present study, en bloc biopsy combined with MRI demonstrated that fasciitis is evident early after the onset of muscle symptoms in DM. Allen et al speculated that fasciitis may represent an early lesion in the evolution of DM (15). To our knowledge, this is the first study demonstrating fasciitis as an early lesion of DM. In contrast, fasciitis was not histopathologically detected in any of the 6 patients with other rheumatic diseases, including the 3 patients with PM. Therefore, fasciitis may be a lesion specific to DM rather than to YOSHIDA ET AL PM. However, the number of patients with PM was too small to accurately determine the specific association of fasciitis with DM. Further investigation is warranted to address this issue. Thus, fasciitis was histopathologically confirmed in most of the patients with adult-onset DM and recognized as a common lesion that appears early after the onset of muscle symptoms in DM. The fascial microvasculature is likely to be the primary site of inflammatory cell infiltration in DM. The results of MRI suggest that inflammation in myopathy accompanying DM progresses from the fascia into the muscle. Muscle symptoms such as myalgia in DM may be attributed to fasciitis when the muscle biopsy reveals a lack of evidence of myositis. ACKNOWLEDGMENTS We are grateful to the doctors at the Department of Plastic and Reconstructive Surgery, Jikei University School of Medicine, for their assistance in performing the en bloc biopsy, and the doctors and staff at the Department of Pathology, Clinical Service, Jikei University School of Medicine, for their assistance with the immunohistochemical staining. AUTHOR CONTRIBUTIONS All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Yoshida had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study conception and design. Yoshida, Kurosaka. Acquisition of data. Yoshida, Kurosaka, Takahashi, Hirai, Noda, Ukichi, Furuya, Yanagimachi, Kingetsu, Yamada. Analysis and interpretation of data. Yoshida, Joh, Matsushima, Fukuda. REFERENCES 1. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med 1975;292:403–7. 2. Mastaglia FL, Ojeda VJ. Inflammatory myopathies: Part 1. Ann Neurol 1985;17:215–27. 3. Whitaker JN. Inflammatory myopathy: a review of etiologic and pathogenetic factors. Muscle Nerve 1982;5:573–92. 4. Carpenter S, Karpati G. The major inflammatory myopathies of unknown cause. Pathol Annu 1981;16:205–37. 5. Whitaker JN, Engel WK. Vascular deposits of immunoglobulin and complement in idiopathic inflammatory myopathy. N Engl J Med 1972;286:333–8. 6. Kissel JT, Mendell JR, Rammohan KW. Microvascular deposition of complement membrane attack complex in dermatomyositis. N Engl J Med 1986;314:329–34. 7. Crowson AN, Magro CM. The role of microvascular injury in the pathogenesis of cutaneous lesions of dermatomyositis. Hum Pathol 1996;27:15–9. 8. Dalakas MC. Polymyositis, dermatomyositis and inclusion-body myositis. N Engl J Med 1991;325:1487–98. FASCIITIS AS A COMMON LESION OF DERMATOMYOSITIS 9. Dubowitz V, Sewry CA. Inflammatory myopathies. In: Muscle biopsy: a practical approach. 3rd ed. Philadelphia: Saunders Elsevier; 2007. p. 519–39. 10. Engel AG, Hohlfeld R. The polymyositis and dermatomyositis syndromes. In: Engel AG, Franzini-Armstrong C, editors. Myology. New York: McGraw-Hill; 2004. p. 1321–66. 11. Crowe WE, Bove KE, Levinson JE, Hilton PK. Clinical and pathogenetic implications of histopathology in childhood polydermatomyositis. Arthritis Rheum 1982;25:126–39. 12. Kimball AB, Summers RM, Turner M, Dugan EM, Hicks J, Miller FW, et al. Magnetic resonance imaging detection of occult skin and subcutaneous abnormalities in juvenile dermatomyositis: implications for diagnosis and therapy. Arthritis Rheum 2000;43: 1866–73. 13. Adams EM, Chow CK, Premkumar A, Plotz PH. The idiopathic inflammatory myopathies: spectrum of MR imaging findings. Radiographics 1995;15:563–74. 14. Krug B, Kugel H, Schulze HJ, Krahe T, Gieseke J, Lackner K. High-resolution MR imaging of the cutis and subcutis: histological correlation. Acta Radiol 1998;39:547–53. 15. Allen E, Schmahmann S, Sauser D, Barkhuizen A. Fasciitis in amyopathic dermatomyositis. J Clin Rheumatol 2003;9:51–3. 16. Tsuruta Y, Ikezoe K, Nakagaki H, Shigeto H, Kawajiri M, Ohyagi Y, et al. A case of dermato-fasciitis: amyopathic dermatomyositis associated with fasciitis. Clin Rheumatol 2004;23:160–2. 17. Kaufman LD, Gruber BL, Gerstman DP, Kaell AT. Preliminary observations on the role of magnetic resonance imaging for polymyositis and dermatomyositis. Ann Rheum Dis 1987;46: 569–72. 18. Park JH, Vital TL, Ryder NM, Hernanz-Schulman M, Partain CL, Price RR, et al. Magnetic resonance imaging and P-31 magnetic resonance spectroscopy provide unique quantitative data useful in the longitudinal management of patients with dermatomyositis. Arthritis Rheum 1994;37:736–46. 19. Fleckenstein JL, Reimers CD. Inflammatory myopathies: radiologic evaluation. Radiol Clin North Am 1996;34:427–39. 20. Gerami P, Schope JM, McDonald L, Walling HW, Sontheimer RD. A systematic review of adult-onset clinically amyopathic dermatomyositis (dermatomyositis sine myositis): a missing link within the spectrum of the idiopathic inflammatory myopathies. J Am Acad Dermatol 2006;54:597–613. 3759 21. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, et al, and the European Study Group on Classification Criteria for Sjögren’s Syndrome. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American–European Consensus Group. Ann Rheum Dis 2002;61:554–8. 22. Gherardi RK, Coquet M, Cherin P, Authier FJ, Laforet P, Belec L, et al, Groupe d’Etudes et Recherche sur les Maladies Musculaires Acquises et Dysimmunitaires (GERMMAD) de l’Association Française contre les Myopathies (AFM). Macrophagic myofasciitis: an emerging entity. Lancet 1998;352:347–52. 23. Grundtman C, Tham E, Ulfgren AK, Lundberg IE. Vascular endothelial growth factor is highly expressed in muscle tissue of patients with polymyositis and patients with dermatomyositis. Arthritis Rheum 2008;58:3224–38. 24. Olsen NJ, Park JH. Inflammatory myopathies: issues in diagnosis and management [review]. Arthritis Care Res 1997;10:200–7. 25. Olsen NJ, Park JH. MRS and NIRS for muscle disease evaluation. Bull Rheum Dis 1995;44:4–7. 26. Park JH, Kari S, King LE Jr, Olsen NJ. Analysis of 31P MR spectroscopy data using artificial neural networks for longitudinal evaluation of muscle diseases: dermatomyositis. NMR Biomed 1998;11:245–56. 27. Chung YL, Wassif WS, Bell JD, Hurley M, Scott DL. Urinary levels of creatine and other metabolites in the assessment of polymyositis and dermatomyositis. Rheumatology (Oxford) 2003; 42:298–303. 28. Engel AG, Arahata K. Monoclonal antibody analysis of mononuclear cells in myopathies. II: Phenotypes of autoinvasive cells in polymyositis and inclusion body myositis. Ann Neurol 1984;16: 209–15. 29. Mantegazza R, Bernasconi P. Cellular aspects of myositis. Curr Opin Rheumatol 1994;6:568–74. 30. Greenberg SA, Pinkus JL, Pinkus GS, Burleson T, Sanoudou D, Tawil R, et al. Interferon-␣/␤-mediated innate immune mechanisms in dermatomyositis. Ann Neurol 2005;57:664–78. 31. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides: proposal of an international consensus conference. Arthritis Rheum 1994;37: 187–92.