Polymyositis/dermatomyositis Research Articles

The Clinical Characteristics of Two Anti-OJ (Anti-Isoleucyl-tRNA Synthetase) Autoantibody-Positive Interstitial Lung Disease Patients with Polymyositis/Dermatomyositis

We herein report the clinical and laboratory characteristics of two anti-OJ (anti-isoleucyl-tRNA synthetase) autoantibody-positive interstitial lung disease patients with polymyositis/dermatomyositis (PM/DM). We compared these characteristics with previously published findings. Previous reports and our present cases show that anti-OJ autoantibody-positive interstitial lung disease (ILD) patients with PM/DM lack the manifestations of Raynaud's phenomenon and sclerodactyly and show good prognoses and responses to glucocorticoid therapy. These results indicate that the presence of anti-OJ autoantibodies may be useful for predicting the prognosis of ILD and its clinical course in PM/DM patients.

Serum level of soluble CX3CL1/fractalkine is elevated in patients with polymyositis and dermatomyositis, which is correlated with disease activity

IntroductionPolymyositis (PM) and dermatomyositis (DM) are chronic inflammatory muscle diseases, in which chemokines are thought to contribute to inflammatory cell migration into muscle. In this study, we retrospectively analyzed the expressions of CX3CL1/fractalkine and its corresponding receptor, CX3CR1, in muscle and lung with interstitial lung disease (ILD) of PM patients and DM patients, and determined the correlation between serum soluble CX3CL1 level and disease activity.MethodsExpressions of CX3CL1 and CX3CR1 in muscle and lung tissue were analyzed by immunohistochemistry. Serum CX3CL1 concentrations were measured by ELISA. For evaluation of patients' disease activity, serum creatinine kinase, manual muscle testing, and the alveolar-arterial oxygen pressure difference were used independently.ResultsCX3CL1 was expressed on infiltrated mononuclear cells and endothelial cells in muscle affected by PM and DM and in lung with ILD, whereas CX3CR1 was expressed on some CD4+ T cells, a majority of CD8+ T cells, and most macrophages in muscle, and on infiltrated mononuclear cells in the lung. Serum soluble CX3CL1 was significantly higher in PM patients and DM patients than in healthy controls. The CX3CL1 level was correlated with serum creatinine kinase and manual muscle testing score. In patients with PM and DM with ILD, serum CX3CL1 was also correlated with alveolar-arterial oxygen pressure difference. Furthermore, CX3CL1 was significantly decreased after conventional treatment.ConclusionsThe interaction between CX3CL1 and CX3CR1 might contribute to the inflammatory cell infiltration into affected muscle and lung with ILD in PM patients and DM patients. Serum CX3CL1 level could be a surrogate marker of disease activity.

Autoantibodies to transcription intermediary factor (TIF)1β associated with dermatomyositis

IntroductionMyositis specific autoantibodies are associated with unique clinical subsets and are useful biomarkers in polymyositis/dermatomyositis (PM/DM). A 120 kD protein recognized by certain patients with DM was identified and clinical features of patients with this specificity were characterized.MethodsThe 120 kD protein recognized by a prototype serum was purified and identified by mass spectrometry and immunological methods. Autoantibody to this 120 kD protein was screened in sera from 2,356 patients with various diagnoses from four countries, including 254 PM/DM, by immunoprecipitation of 35S-methionine labeled K562 cell extracts. Clinical information of patients with this specificity was collected.ResultsThe 120 kD protein, which exactly comigrated with PL-12, was identified as transcription intermediary factor TIF1β (TRIM28) by mass spectrometry and validated by immunoassays. By immunofluorescence, anti-TIF1β positivity showed a fine-speckled nuclear staining pattern. Four cases of anti-TIF1β were identified; all are women, one each in a Japanese, African American, Caucasian, and Mexican individual. Three had a diagnosis of DM and one case was classified as having an undifferentiated connective tissue disease with an elevated CPK but without significant muscle symptoms. This individual also had a history of colon cancer, cervical squamous metaplasia and fibroid tumors of the uterus. Myopathy was mild in all cases and resolved without treatment in one case. The anti-TIF1β specificity was not found in other conditions.ConclusionsAnti-TIF1β is a new DM autoantibody associated with a mild form of myopathy. Whether it has an association with malignancy, as in the case of anti-TIF1γ, or other unique features will need to be evaluated in future studies.

Anti-synthetase syndrome presenting as cryptogenic organizing pneumonia

Interstitial lung disease (ILD) is a unique group of lung diseases that can be associated with inflammatory conditions, such as polymyositis-dermatomyositis (PM-DM). Presentation of PM-DM with ILD is not uncommon but clinical and radiological features can be similar to other conditions (e.g. atypical pneumonia) and can be challenging to diagnose. Delayed diagnosis of PM-DM can be associated with progression of pulmonary involvement and potentially increase morbidity. We report a patient presenting with pulmonary symptoms who had positive anti-Jo-1 antibodies and cryptogenic organizing pneumonia features on biopsy, which is a rare reported finding.

Common Pathways of Autoimmune Inflammatory Myopathies and Genetic Neuromuscular Disorders

It has been shown that many hereditary motor neuron diseases are caused by mutation of RNA processing enzymes. Survival of motor neuron 1 (SMN1) is well-known as a causative gene for spinal muscular atrophy (SMA) and mutations of glycyl- and tyrosyl-tRNA synthetases are identified as a cause of distal SMA and Charcot-Marie-Tooth disease. Why and how the dysfunction of these ubiquitously expressed genes involved in RNA processing can cause a specific neurological disorder is not well understood. Interestingly, SMN complex has been identified recently as a new target of autoantibodies in polymyositis (PM). Autoantibodies in systemic rheumatic diseases are clinically useful biomarkers associated with a particular diagnosis, subset of a disease, or certain clinical characteristics. Many autoantibodies produced in patients with polymyositis/dermatomyositis (PM/DM) target RNA-protein complexes such as aminoacyl tRNA synthetases. It is interesting to note these same RNA-protein complexes recognized by autoantibodies in PM/DM are also responsible for genetic neuromuscular disease. Certain RNA-protein complexes are also targets of autoantibodies in paraneoplastic neurological disorders. Thus, there are several interesting associations between RNA-processing enzymes and neuromuscular disorders. Although pathogenetic roles of autoantibodies to intracellular antigens are generally considered unlikely, understanding the mechanisms of antigen selection in a particular disease and specific neurological symptoms caused by disruption of ubiquitous RNA-processing enzyme may help identify a common path in genetic neuromuscular disorders and autoimmunity in inflammatory myopathies.

Short‐term and long‐term outcomes of interstitial lung disease in polymyositis and dermatomyositis: A series of 107 patients

This study was undertaken to assess the characteristics and outcome of interstitial lung disease (ILD) in polymyositis/dermatomyositis (PM/DM) and to determine variables predictive of ILD deterioration in PM/DM. Among 348 consecutive patients with PM/DM, 107 patients with ILD were identified by medical records search in 4 medical centers. All patients underwent pulmonary function tests (PFTs) and pulmonary high-resolution computed tomography (HRCT) scan. ILD onset preceded PM/DM clinical manifestations in 20 patients, was identified concurrently with PM/DM in 69 patients, and occurred after PM/DM onset in 18 patients. Patients with ILD could be divided into 3 groups according to their presenting lung manifestations: patients with acute lung disease (n = 20), patients with progressive-course lung signs (n = 55), and asymptomatic patients with abnormalities consistent with ILD evident on PFTs and HRCT scan (n = 32). We observed that 32.7% of the patients had resolution of pulmonary disorders, whereas 15.9% experienced ILD deterioration. Factors that predicted a poor ILD prognosis were older age, symptomatic ILD, lower values of vital capacity and diffusing capacity for carbon monoxide, a pattern of usual interstitial pneumonia on HRCT scan and lung biopsy, and steroid-refractory ILD. The mortality rate was higher in patients with ILD deterioration than in those without ILD deterioration (47.1% versus 3.3%). Our findings indicate that ILD results in high morbidity in PM/DM. Our findings also suggest that more aggressive therapy may be required in PM/DM patients presenting with factors predictive of poor ILD outcome.

Disease-related Risk of Vertebral Fracture During Glucocorticoid Treatment of Collagen Vascular Diseases

To the Editor: Collagen vascular diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren’s syndrome (SS), systemic sclerosis (SSc)/mixed connective tissue disease (MCTD), polymyositis/dermatomyositis (PM/DM), and microscopic polyangiitis, are chronic and sometimes involve multiple organs, and are thus occasionally life-threatening. Immunosuppressive treatment with longterm high-dose glucocorticoids is necessary, but the treatment causes a high incidence of osteoporosis1,2,3. Recently, we demonstrated that patients treated with longterm high-dose glucocorticoids have a high risk of symptomatic vertebral fractures in collagen vascular diseases, based on the analysis of the Chiba-Shimoshizu Rheumatic Cohort4,5. The chronic and systemic inflammation in patients with RA and SLE has been recognized as causing secondary osteoporosis independently of glucocorticoids6, and many studies demonstrated that patients with RA have lower bone mineral density (BMD) and an increased risk of fracture7,8,9. However, it was not known whether there is a disease-specific or disease-related risk of osteoporotic fracture under glucocorticoid treatment among the collagen vascular diseases. We investigated the disease-specific or disease-related risk for osteoporotic symptomatic vertebral fracture by focusing on women treated with high-dose glucocorticoids for the long term for collagen vascular diseases, subanalyzing a cohort at Shimoshizu National Hospital in Japan. The study subjects were newly treated with an initial dose of > 20 mg/day prednisolone (PSL) equivalent for at least 6 months without prior prophylactic treatment with bisphosphonate, hormone replacement therapy, or selective estrogen receptor modulator to prevent bone loss. We defined glucocorticoid dose increase as the reintroduction of ≥ 20 mg/day of glucocorticoid (PSL equivalent) due to increased disease activity in patients whose doses were once tapered to < 20 mg/day. Symptomatic vertebral fracture was defined as vertebral deformity that was confirmed … Address correspondence to Dr. I. Tatsuno, Department of Clinical Cell Biology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan. E-mail: ichiro-tatsuno{at}faculty.chiba-u.jp

Myositis disease activity tool in Chinese patients with polymyositis/dermatomyositis

To test the reliability, discriminating validity and clinical value of myositis disease activity tool in Chinese patients with polymyositis/dermatomyositis (PM/DM). Fifty-four PM/DM patients (PM, n = 18; DM, n = 36) at our hospital between January 2009 and June 2010 were enrolled into this prospective study. The disease activity was assessed by the MDAAT (myositis disease activity assessment tool). The reliability and discriminating validity were assessed with test-retest reliability, interrater reliability and t-test analysis. The reliability analysis of MDAAT indicated 8 items (constitutional, cutaneous, skeletal, gastrointestinal, pulmonary, cardiovascular, muscular & global) had excellent reliability, the ICC (intraclass correlation coefficient) was 0.72 (95%CI: 0.57, 0.83), 0.88 (95%CI: 0.79, 0.93), 0.83 (95%CI: 0.72, 0.90), 0.62 (95%CI: 0.42, 0.76), 0.81 (95%CI: 0.70, 0.89), 0.59 (95%CI: 0.38, 0.74), 0.85 (95%CI: 0.75, 0.91) and 0.84 (95%CI: 0.73, 0.90) respectively. MDAAT had excellent discrimination validity in all items except for cardiovascular ones. With excellent reliability and discriminating validity, MDAAT may be used to assess the disease activity and therapeutic effects of Chinese PM/DM patients.

Jaw muscle weakness: A differential indicator of neuromuscular weakness—Preliminary observations

Flaccid quadriparesis is a common neurological problem. Guillain-Barré syndrome Guillain-Barre syndrome (GBS), polymyositis/dermatomyositis (PM/DM), generalized myasthenia gravis (MG), and hypokalemic periodic paralysis (HPP) constitute the majority of cases of flaccid quadriparesis. Few patients from any of these disease groups lack the cardinal clinical features. We established clinical marker(s) that might have significant discriminating power for diagnosis. Forty-six patients satisfied all of our criteria. Cases were evaluated clinically followed by laboratory and electrophysiological study, and, in selected cases, muscle histopathology. Twenty-four patients had GBS, 9 had MG, 7 had PM/DM, and 6 had HPP. Jaw-opening weakness was found in 71.4% of PM/DM, 83.3% of HPP, and 4.1% of GBS cases. Jaw-closing weakness was found in 88.8% of MG cases. Presence of jaw-closing weakness pointed toward MG, whereas presence of jaw-opening weakness suggested muscle disease (PM/DM and HPP). GBS patients very rarely had jaw muscle weakness.

Expression of interferon and its correlation with clinical features in idiopathic inflammatory myopathies

To detect the expression levels of interferons IFNα, IFNβ and IFNγ in the peripheral blood and muscle of patients with idiopathic inflammatory myopathies (IIM) so as to analyze their relationships with organ manifestations. The serum levels of IFNα, IFNβ, IFNγ and anti-Jo-1antibody were measured with ELISA (enzyme-linked immunosorbent assay). And the method of SYBR green dye based real-time quantitative PCR (polymerase chain reaction) was used to compare the expression levels of IFNα, IFNβ, interferon α receptor 1 (IFNαR1), signal transducer and activator of transcription 1 (STAT1) in the IIM patients and normal controls. The serum levels of IFNα (50.2 ± 21.0) ng/L and IFNβ (10.7 ± 5.4) ng/L in IIM patients were significantly higher than those in normal controls (18.6 ± 3.6) ng/L, (3.9 ± 0.8) ng/L (P < 0.01). And the serum levels of IFNα (55.7 ± 21.9) ng/L and IFNβ (11.3 ± 2.3) ng/L in DM patients were significantly higher than those in PM patients (26.1 ± 8.2) ng/L, (6.2 ± 3.5) ng/L (P < 0.05). The serum levels of IFNα and IFNβ correlated with the presence of skin rash (P < 0.05). And their serum concentrations correlated positively with erythrocyte sedimentation rate (r = 0.442, P = 0.000; r = 0.562, P = 0.000) and C-reactive protein (r = 0.348, P = 0.004; r = 0.432, P = 0.005)respectively. The serum levels of IFNα and IFNβ decreased significantly after treatment in 12 PM/DM (polymyositis/dermatomyositis) patients (P < 0.01). The mRNA expression levels of IFNα, IFNβ, IFNαR1 and STAT1 in PM/DM patients were higher than those in normal controls (P < 0.05). The expression levels of IFNα and IFNβ in PM/DM patients are significantly higher than those in normal controls. And the increments had correlations with disease activity and severity. STAT1 has been implicated in signal transduction of IFNα and IFNβ in the muscles of PM/DM patients.

Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis

The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0–21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort.

High frequency of osteoporosis and fractures in women with dermatomyositis/polymyositis

Bone mass was only previously studied in juvenile dermatomyositis/polymyositis (DM/PM) patients. Therefore, the objective this study was to evaluate the prevalence of osteoporosis and fractures in adult DM/PM. Forty female DM/PM and 78 age-, gender-, and BMI-matched healthy controls were studied. Medical charts and clinical interviews of all patients were evaluated for demographic and clinical data, including disease activity, cumulative doses of glucocorticoid, menarche and menopause age, and fractures. Bone mineral density (BMD) using dual X-ray absorptiometry (DXA) were measured at lumbar spine (L1-L4) and hip. A decreased BMD in lumbar spine [0.902 (0.136) vs. 0.965 (0.141) g/cm(2), P=0.022] and femoral neck [0.729 (0.12) vs. 0.784 (0.127) g/cm(2), P=0.027] was observed in patients compared to controls. In addition, osteoporosis was more frequent in patients than in controls in both lumbar spine (20 vs. 3.8%, P=0.007) and the femoral neck (27.5 vs. 10.3%, P=0.016). Moreover, a high prevalence of fractures was found in patients in comparison to healthy subjects (17.9 vs. 5.1%, P=0.040; OR=3.92; CI 95%:1.07-14.33). Comparing DM/PM patients with (n=17) and without (n=23) osteoporosis/fractures, significant differences were observed regarding age [56.8 (11.9) vs. 48.3 (13.2) years, P=0.042], weight [62.05 (13.56) vs. 71.51 (11.46) kg, P=0.022] and frequency of post menopausal women (94.1 vs. 65.2%, P=0.0002). No differences were observed concerning height, lean mass, total fat mass, disease activity, mean value of creatine kinase, cumulative glucocorticoid dose, or bisphosphonate use. Logistic regression analysis revealed a negative association between the presence of osteoporosis/fractures and weight (OR: 0.92, 95% CI: 0.85-0.98; P=0.016). This is the first study that analyzed bone mass in adult DM/PM patients and it demonstrated that about one quarter of these patients have osteoporosis/fracture.

Review Series: Aspects of Interstitial lung disease: Connective tissue disease-associated interstitial lung disease: How does it differ from IPF? How should the clinical approach differ?

The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.

Open-label trial and randomized, double-blind, placebo-controlled, crossover trial of hydrogen-enriched water for mitochondrial and inflammatory myopathies

BackgroundMolecular hydrogen has prominent effects on more than 30 animal models especially of oxidative stress-mediated diseases and inflammatory diseases. In addition, hydrogen effects on humans have been reported in diabetes mellitus type 2, hemodialysis, metabolic syndrome, radiotherapy for liver cancer, and brain stem infarction. Hydrogen effects are ascribed to specific radical-scavenging activities that eliminate hydroxyl radical and peroxynitrite, and also to signal-modulating activities, but the detailed molecular mechanisms still remain elusive. Hydrogen is a safe molecule that is largely produced by intestinal bacteria in rodents and humans, and no adverse effects have been documented.MethodsWe performed open-label trial of drinking 1.0 liter per day of hydrogen-enriched water for 12 weeks in five patients with progressive muscular dystrophy (PMD), four patients with polymyositis/dermatomyositis (PM/DM), and five patients with mitochondrial myopathies (MM), and measured 18 serum parameters as well as urinary 8-isoprostane every 4 weeks. We next conducted randomized, double-blind, placebo-controlled, crossover trial of 0.5 liter per day of hydrogen-enriched water or placebo water for 8 weeks in 10 patients with DM and 12 patients with MM, and measured 18 serum parameters every 4 weeks.ResultsIn the open-label trial, no objective improvement or worsening of clinical symptoms was observed. We, however, observed significant effects in lactate-to-pyruvate ratios in PMD and MM, fasting blood glucose in PMD, serum matrix metalloproteinase-3 (MMP3) in PM/DM, and serum triglycerides in PM/DM. In the double-blind trial, no objective clinical effects were observed, but a significant improvement was detected in lactate in MM. Lactate-to-pyruvate ratios in MM and MMP3 in DM also exhibited favorable responses but without statistical significance. No adverse effect was observed in either trial except for hypoglycemic episodes in an insulin-treated MELAS patient, which subsided by reducing the insulin dose.ConclusionsHydrogen-enriched water improves mitochondrial dysfunction in MM and inflammatory processes in PM/DM. Less prominent effects with the double-blind trial compared to the open-label trial were likely due to a lower amount of administered hydrogen and a shorter observation period, which implies a threshold effect or a dose-response effect of hydrogen.

Frequent coexistence of anti-topoisomerase I and anti-U1RNP autoantibodies in African American patients associated with mild skin involvement: a retrospective clinical study

IntroductionThe presence of anti-topoisomerase I (topo I) antibodies is a classic scleroderma (SSc) marker presumably associated with a unique clinical subset. Here the clinical association of anti-topo I was reevaluated in unselected patients seen in a rheumatology clinic setting.MethodsSera from the initial visit in a cohort of unselected rheumatology clinic patients (n = 1,966, including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) were screened by radioimmunoprecipitation. Anti-topo I-positive sera were also tested with immunofluorescence and RNA immunoprecipitation.ResultsTwenty-five (15 Caucasian, eight African American, two Latin) anti-topo I positive patients were identified, and all except one met the ACR SSc criteria. Coexistence of other SSc autoantibodies was not observed, except for anti-U1RNP in six cases. When anti-topo I alone versus anti-topo I + U1RNP groups were compared, African American (21% vs. 67%), overlap with SLE (0 vs. 50%; P = 0.009) or PM/DM (0 vs. 33%; P = 0.05) or elevated creatine phosphokinase (CPK) (P = 0.07) were more common in the latter group. In comparison of anti-topo I-positive Caucasians versus African Americans, the latter more frequently had anti-U1RNP (13% vs. 50%), mild/no skin changes (14% vs. 63%; P = 0.03) and overlap with SLE (0 vs. 38%; P = 0.03) and PM/DM (0 vs. 25%; P = 0.05).ConclusionsAnti-topo I detected by immunoprecipitation in unselected rheumatology patients is highly specific for SSc. Anti-topo I coexisting with anti-U1RNP in African American patients is associated with a subset of SLE overlapping with SSc and PM/DM but without apparent sclerodermatous changes.

Atypical clinical presentation of a subset of patients with anti-RNA polymerase III - non-scleroderma cases associated with dominant RNA polymerase I reactivity and nucleolar staining

IntroductionAnti-RNA polymerase III (RNAP III) antibodies are highly specific markers of scleroderma (systemic sclerosis, SSc) and associated with a rapidly progressing subset of SSc. The clinical presentation of anti-RNAP III positive patients, onset of Raynaud's phenomenon (RP) and SSc in unselected patients in a rheumatology clinic were evaluated.MethodsAutoantibodies in sera from 1,966 unselected patients (including 434 systemic lupus erythematosus (SLE), 119 SSc, 85 polymyositis/dermatomyositis (PM/DM)) in a rheumatology clinic were screened by radioimmunoprecipitation. Anti-RNAP III positive sera were also tested by immunofluorescence antinuclear antibodies and anti-RNAP III ELISA. Medical records of anti-RNAP III positive patients were reviewed.ResultsAmong 21 anti-RNAP III positive patients, 16 met the American College of Rheumatology (ACR) SSc criteria at the initial visit but 5 did not; diagnoses were vasculitis, early polyarthritis, renal failure with RP, interstitial lung disease, and Sjögren's syndrome. The first two patients developed rapidly progressive diffuse SSc. An additional case presented with diffuse scleroderma without RP and RP developed two years later. Anti-RNAP III antibodies in these 6 cases of atypical clinical presentation were compared with those in 15 cases of typical (SSc with RP) cases. Anti-RNAP III levels by ELISA were lower in the former group (P = 0.04 by Mann-Whitney test) and 3 of 6 were negative versus only 1 of 15 negative in the latter (P < 0.05 by Fisher's exact test). Three cases of non-SSc anti-RNAP III positive patients had predominant reactivity with RNAP I with weak RNAP III reactivity and had a strong nucleolar staining. Three anti-RNAP III patients, who did not have RP at the initial visit, developed RP months later. Scleroderma developed prior to RP in 5 out of 16 (31%) in the anti-RNAP III group, but this was rare in patients with other autoantibodies. The interval between the onset of RP to scleroderma was short in anti-RNAP III positive patients.ConclusionsAnti-RNAP III antibodies are highly specific for SSc; however, a subset of anti-RNAP III positive patients do not present as typical SSc. The interval between RP and scleroderma in this group is short, and 31% of patients developed scleroderma prior to RP in this group. Anti-RNAP III positive patients may not present as typical SSc and detecting anti-RNAP III may have predictive value.

Serum concentration of interleukin 15, interleukin 2 receptor and TNF receptor in patients with polymyositis and dermatomyositis: correlation to disease activity

Cytokines are implied in polymyositis/dermatomyositis (PM/DM) pathogenesis. Our aim was to evaluate the serum levels of interleukin-15 (IL-15), soluble receptors for IL-2 (sIL-2R) and TNF-alpha type 1 receptor (sTNF-R1) in PM/DM patients and their relation to disease activity and clinical symptoms. Thirty-eight patients who met definite or probable criteria of Bohan and Peter for DM/PM were included into the study. Results in patients with active (41 observations) and inactive disease (24 observations) were compared with control (15 subjects). The median level of IL-15 was 47.6 ± 170 pg/ml in active patients, 25.15 ± 240 pg/ml in inactive and 28.5 ± 28.89 pg/ml in controls. We demonstrated significant differences between active patients and controls in levels of IL-15 (0.016, 95%CI 1.39–57.1). The median level of sIL-2R was 314 ± 388, 235.3 ± 269 and 144.3 ± 152.9 pg/ml, and the median level of sTNF-R1 was 350 ± 388; 294.7 ± 204.7; 209.5 ± 105.9 pg/ml in active, inactive and control subjects, respectively. There were significantly higher serum levels of these cytokines in active patients than in control subjects (for sIL-2R P = 0.05, CI95% 0.4–331; and sTNF-R1 P = 0.031, CI95% 15.1–321.5). The interleukin levels did not differ between inactive patients and controls. Elevation of IL-15, sIL2-R and sTNF-R1 in active patients provides preliminary evidence for the activation of inflammatory response during PM/DM flares. Further studies may be needed to explain the mechanisms driving these diseases.

Intravenous immunoglobulins for steroid‐refractory esophageal involvement related to polymyositis and dermatomyositis: A series of 73 patients

To assess the long-term outcome of esophageal complications in the group of patients receiving intravenous immunoglobulins (IVIG) for the treatment of severe steroid-refractory esophageal involvement related to polymyositis/dermatomyositis (PM/DM). We retrospectively reviewed the medical records of 73 patients (39 with PM, 34 with DM) with steroid-resistant esophageal involvement. Esophageal involvement was evaluated by clinical and manometric investigations. Seventy-three patients with steroid-refractory esophageal involvement related to PM/DM received IVIG therapy (2 gm/kg monthly). The median interval between PM/DM diagnosis and the onset of esophageal complications was 6 months. The most common clinical manifestations revealing esophageal dysfunction were dysphagia (69.9%), coughing while eating (61.6%), and gastroesophageal reflux into the pharynx and/or mouth (34.2%). Twenty-five patients exhibited life-threatening esophageal complications requiring exclusive enteral feeding; 33 patients (45.2%) with esophageal impairment developed aspiration pneumonia. Sixty patients (82.2%) exhibited resolution of esophageal clinical manifestations, leading to a return to normal oral feeding and ablation of feeding enteral tubes. Four other patients (5.5%) improved, although they still experienced mild dysphagia intermittently. Because of impaired cricopharyngeal muscle relaxation, another patient successfully underwent cricopharyngeal myotomy. Eight patients died from aspiration pneumonia (n=6) and cancer (n=2). Muscle weakness, thoracic myopathy, and aspiration pneumonia were independent predictive factors of IVIG-treated esophageal complications in PM/DM patients. Our findings indicate that IVIG should be considered in life-threatening esophageal impairment complicating steroid-resistant PM/DM. We also suggest that combined therapy of IVIG and high-dose steroids may be the first-line therapy in PM/DM patients with life-threatening esophageal manifestations.

Incidence and predictive factors for malignancies in 136 Japanese patients with dermatomyositis, polymyositis and clinically amyopathic dermatomyositis

The aim of this study was to define the standardized incidence ratio (SIR) of malignancy and the potential risk factors of concomitant malignancies in patients with inflammatory myopathies, including clinically amyopathic dermatomyositis (CADM). A total of 145 patients diagnosed with either dermatomyositis/polymyositis (DM/PM) or CADM at our institute between 1984 and 2002 were enrolled in the study. The demographic, clinical and laboratory features of the patients at the time of DM/PM or CADM diagnosis were compared between patients with and without malignancies, respectively. Multivariate analysis by logistic regression was used to determine the independent risk factors for the development of malignancies in DM/PM patients. Malignancy was found in 17 of 70 patients with DM (24%), three of 15 patients with CADM (20%), and three of 51 patients with PM (6%). Gastric cancer (8/23) was the most common malignancy. Compared with general population, the SIR of malignancies was 13.8 (range 9.0-21.1). The patients who developed malignancies were older (61.5 vs. 51.1 years; P < 0.005), presented more often with dysphagia (61 vs. 15%; P < 0.0001) and were less likely to have the complication of interstitial lung disease (30 vs. 60%; P < 0.05). These features were independent predictive factors for developing malignancies in multiple logistic regression analysis. The results of our study confirm that CADM in addition to DM was associated with high rates of malignancy among our patient cohort.

Increased Fracture Risk in Patients with Rheumatic Disorders and Other Inflammatory Diseases — A Case-Control Study with 53,108 Patients with Fracture: Table 1.

To identify the risk of hip and vertebral fractures in patients with rheumatic disorders (RD) and inflammatory bowel diseases (IBD). This population-based case-control study assessed the fracture risk of patients with rheumatoid arthritis, juvenile idiopathic arthritis (JIA), ankylosing spondylitis (AS), systemic lupus erythematosus, polymyositis/dermatomyositis (PM/DM), systemic sclerosis (SSc), Crohn's disease, and ulcerative colitis (UC). The study cohort comprised 53,108 patients with fracture (66% women) and 370,602 age-matched and sex-matched controls. Conditional logistic regression analysis was performed and results were expressed as OR with corresponding 95% CI. There was a statistically significant increased fracture risk for all RD and for IBD compared with controls. The magnitude of fracture risk was higher for patients with RD (OR 3, 95% CI 2.9-3.2) than for those with IBD (OR 1.6, 1.4-1.8). The OR in RD ranged from 2.6 (1.3-4.9) for SSc to 4 (3.4-4.6) for AS. The largest increased fracture risk for vertebral fractures was seen in AS (OR 7.1, 6-8.4) and for hip fractures in JIA (OR 4.1, 2.4-6.9). Our results highlight the existence of an increased fracture risk from a variety of underlying causes in patients with RD and IBD. In many inflammatory diseases, implementation of fracture prevention strategies may be beneficial.