Responsiveness and meaningful thresholds of PROMIS pain interference, fatigue, and physical function forms in adults with idiopathic inflammatory myopathies: Report from the OMERACT Myositis Working Group.

BACKGROUND: A series of qualitative studies conducted by the OMERACT Myositis Working Group identified pain interference, fatigue, and physical function as highly important life impact domains for adults with idiopathic inflammatory myositis (IIM). In this study, our goal was to assess the responsiveness and minimal important difference of PROMIS pain interference (6a), fatigue (7a), and physical function (8b). METHODS: Adults with IIM from USA, Netherlands, Korea, Sweden, and Australia with two "clinical" visits were enrolled in this prospective study. Anchor questions on a Likert scale were collected at baseline, and manual muscle testing (MMT), physician and patient reported global disease activity, and PROMIS instruments were collected at both visits. Responsiveness was assessed with i) ANOVA, ii) paired t-test, effect size and standardized response mean, and iii) Pearson correlation. Minimal important difference (MID), minimal important change (MIC) and minimal detectable change (MDC) values were calculated. RESULTS: 114 patients with IIM (median age 60, 60 % female) completed both visits. Changes in PROMIS instruments were significantly different among anchor categories. Patients who reported improvement had a significant improvement in their PROMIS scores with at least medium effect size, while patients who reported worsening and stability did not show a significant change with weak effect size. PROMIS instruments had weak to moderate correlations with MMT, patient and physician global disease activity. MID was approximately 2-3 points for Pain Interference and 3-4 points for Fatigue and Physical Function forms based on the method used. MIC was approximately 4-5 for improvement of all the instruments, while MDC was 1.7-2 points for Pain Interference and Physical Function and 3.2-3.9 for Fatigue. CONCLUSION: This study provides evidence towards the responsiveness of the PROMIS instruments in a large international prospective cohort of adults with IIM supporting their use as PROMs in adult myositis.

Low health-related quality of life in adult individuals with multiple limb deficiencies compared with population-based reference values.

BACKGROUND: Knowledge on health-related quality of life (HRQoL) in multiple limb deficiencies (LDs) is limited. OBJECTIVES: To investigate self-reported HRQoL in multiple LDs, assess differences between congenital LD and acquired LD and sex, and to evaluate associations between the types of LDs, demographic variables, and HRQoL. STUDY DESIGN: Cross-sectional cohort study. METHODS: A total of 106 individuals with multiple limb deficiencies treated at the EX-Center were invited by mail to fill out the Short Form-36 survey. RESULTS: Responses from 62 participants, mean age ± SD 49.5 ± 14.2, showed that 43 had congenital LD and 19 had acquired LD. Responders reported reduced HRQoL in all Short Form-36 domains except Role-Emotional, compared with reference values (P < 0.05-<0.001). Individuals with a congenital LD reported worse Bodily Pain than acquired LD (P < 0.05), and women reported lower Physical Function than men (P < 0.05). Sick leave was negatively associated with physical composite score. Living in a rural area was positively associated with Mental Health (P < 0.01), and congenital LD was negatively associated with Vitality (P < 0.05). CONCLUSIONS: Individuals with multiple LDs in Sweden have lower HRQoL compared with reference values. There are significant associations between sick leave and physical function, rural living and mental health, and the type of LD and vitality.

Muscle endurance, strength, and active range of motion in patients with different subphenotypes in systemic sclerosis: a cross-sectional cohort study.

OBJECTIVE: Proximal muscle weakness is common in patients with systemic sclerosis (SSc). Dynamic muscle endurance, muscle strength in the lower extremities, and active range of motion (AROM) in the upper extremities are less studied. We investigated functional muscle endurance, strength, and AROM, and explored differences depending on skin and/or lung involvement in SSc patients. METHOD: The study divided 205 patients with limited/diffuse cutaneous systemic sclerosis (lcSSc/dcSSc) into no-mild and moderate-end-stage lung involvement, the latter based on the Medsger disease severity score. Dynamic muscle endurance in shoulder and hip flexion was assessed by the Functional Index-2, lower extremity muscle strength by the Timed-Stands Test (TST), and shoulder-arm AROM by the Functional Shoulder Assessment (FSA). RESULTS: Shoulder and hip flexion muscle endurance were reduced in relation to reference values median (IQR) [53% (27-100%) and 40% (23-90%), respectively, p < 0.001]. Patients with moderate-end-stage lung involvement had less endurance in shoulder [39% (21-71%) and hip flexion 35% (20-70%)] than patients with no-mild lung involvement [57% (33-99%) and 48% (28-100%), p < 0.05]. All patients, regardless of subtype/grouping, needed longer to complete the TST [21 s (17-27 s)] compared to reference values [17 s (15-18 s), p < 0.001], and patients with moderate-end-stage lung involvement had worse TST score than patients with no-mild lung involvement,  [25 s (18-30 s) vs 19 s (16-25 s), p < 0.001]. The FSA sum scores were lower compared with reference values (p < 0.01). DcSSc patients had a lower FSA-sum score [53 (48-57)] than lcSSc patients [57 (52-60), p < 0.01]. CONCLUSION: SSc patients have markedly reduced muscle endurance in the upper and lower extremities, reduced muscle strength in the lower extremities, and impaired AROM in the shoulders and arms. Patients with moderate-end-stage lung involvement had more impaired muscle endurance and strength but no differences were found between lcSSc and dcSSc patients. Not only muscle strength, but also dynamic muscle endurance should be measured in SSc patients.

Self-reported physical capacity and activity in patients with systemic sclerosis and matched controls.

OBJECTIVE: The aim was to investigate differences in self-reported physical capacity and activity between systemic sclerosis (SSc) patients and population-based controls, as well as between patients with normal-mild, or moderate-severe, lung disease and their respective controls. METHOD: The study included 106 patients fulfilling the American College of Rheumatology SSc criteria and 106 controls, individually matched for age and gender. Patients were subdivided into normal-mild and moderate-severe lung disease based on results from pulmonary function tests and SSc severity scale. Participants answered questions regarding physical capacity and activity, exercise, and time spent sitting. RESULTS: SSc patients reported overall lower capacity for walking, jogging, and running (p < 0.001), and more limiting factors for physical capacity than controls (p < 0.001). Both patients with normal-mild and moderate-severe lung disease also reported lower overall physical capacity than their respective controls (p = 0.001, p < 0.001). Normal-mild lung disease patients reported pain more often than their controls (p < 0.05), whereas moderate-severe lung disease patients reported cardiopulmonary disease (p < 0.001) and reduced muscle strength (p = 0.03) as limiting factors for physical capacity more often than their controls. More patients than controls had 'never exercised' for at least 30 min per occasion within the past year (28% vs 15%, p = 0.03); however, there were no differences overall between patients and controls in frequency of exercise, physical activity, or time spent sitting. CONCLUSION: Although SSc patients reported lower physical capacity and more limiting factors for physical capacity than controls, there were no differences in reported physical activity and time spent sitting. Further development of physical activity programmes for SSc patients, especially for patients who never exercise or have physical impairments, is needed.

Physical exercise as a treatment for adult and juvenile myositis.

There is growing evidence to support the safety and efficacy of exercise in patients with adult and juvenile idiopathic inflammatory myopathies. Five randomized controlled trials including adult patients with polymyositis and dermatomyositis (DM) and additional open studies have demonstrated reduced impairment and activity limitation as well as improved quality of life. In addition, recent studies have shown reduced disease activity assessed by consensus disease activity measures and reduced expression of genes regulating inflammation and fibrosis. Furthermore, exercise could improve muscle aerobic capacity as shown by increased mitochondrial enzyme activity. These data suggest that intensive aerobic exercise and resistance training could reduce disease activity and inflammation and improve muscle metabolism. Encouraging results have been reported from available open studies including patients with inclusion body myositis (IBM) and juvenile DM, indicating reduced impairment, activity limitation and improved quality of life also in these patients. Larger studies are needed to increase understanding of the effects of exercise in patients with active, recent-onset polymyositis and DM as well as in patients with IBM and juvenile DM.

Higher proportion of fast-twitch (type II) muscle fibres in idiopathic inflammatory myopathies - evident in chronic but not in untreated newly diagnosed patients.

OBJECTIVE: Polymyositis and dermatomyositis are idiopathic, inflammatory myopathies characterized by proximal muscle fatigue. Conventional immunosuppressive treatment gives a variable response. Biopsies from chronic patients display a low proportion type I and a high proportion of type II muscle fibres. This raised a suspicion that the low proportion of type I fibres might play a role in the muscle fatigue. AIM: To investigate whether the muscle fibre attributes evident in chronic myositis are characteristic for the polymyositis and dermatomyosistis diseases themselves. METHODS: Muscle biopsies were obtained from thigh muscle from untreated patients (n = 18), treated responders (n = 14) and non-responders (n = 6) and from healthy controls (n = 11), respectively. For clinical evaluations, creatine kinase, functional index of myositis and cumulative dose of cortisone were established. RESULTS: Chronic patients had a lower proportion of type I fibres and a higher proportion of type II fibres compared to untreated myositis patients and healthy controls. Fibre cross-sectional area (CSA) did not differ between patients and healthy individuals but all women had a 20% smaller type II fibre CSA compared to men. CONCLUSIONS: Untreated polymyositis and dermatomyositis patients and healthy controls have a different fibre type composition than chronic polymyositis and dermatomyositis patients. Fibre CSA did not differ between healthy controls or any of the patient groups. A low proportion of oxidative muscle fibres can therefore be excluded as a contributing factor causing muscle fatigue at disease onset and the gender difference should be taken into consideration when evaluating fibre CSA in myositis.

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies.

OBJECTIVE: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. METHODS: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. RESULTS: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by >or=20% in three or more variables of the disease activity core set, four were unchanged and two worsened >or=30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. CONCLUSIONS: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

Effects of immunosuppressive treatment on microsomal prostaglandin E synthase 1 and cyclooxygenases expression in muscle tissue of patients with polymyositis or dermatomyositis.

OBJECTIVES: To investigate the expression of microsomal prostaglandin E (PGE) synthase 1 (mPGES-1) and cyclooxygenase (COX) in muscle biopsies from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. METHODS: mPGES-1 and COX expression was evaluated by immunohistochemistry in muscle tissue from healthy individuals and from patients with polymyositis or dermatomyositis before and after conventional immunosuppressive treatment. The number of inflammatory cell infiltrates, T lymphocytes and macrophages was estimated before and after treatment. To localise the mPGES-1 expression double immunofluorescence was performed with antibodies against mPGES-1, CD3, CD68, CD163 and a fibroblast marker. A functional index was used to assess muscle function. RESULTS: In patients with myositis, mPGES-1, COX-2 and COX-1 expression was significantly higher compared to healthy individuals and associated with inflammatory cells. Double immunofluorescence demonstrated a predominant expression of mPGES-1 in macrophages. Conventional immunosuppressive treatment resulted in improved but still lower muscle function than normal. A decreased number of CD68-positive macrophages and reduced COX-2 expression in muscle tissue was also seen. By contrast, following the same treatment no significant changes were observed in muscle tissue regarding number of infiltrates, T lymphocytes, CD163-positive macrophages or mPGES-1 protein levels. CONCLUSIONS: Increased expression of mPGES-1, COX-1 and COX-2 at protein level was observed in muscle tissue from patients with myositis compared to healthy individuals. Conventional immunosuppressive treatment led to a significant downregulation of COX-2 in myositis muscle tissue. However, the expression of mPGES-1 and COX-1 remained unchanged indicating a role of these enzymes in the chronicity of these diseases.

Disease-specific quality indicators, outcome measures and guidelines in polymyositis and dermatomyositis.

Polymyositis and dermatomyositis are chronic inflammatory muscle disorders with frequent involvement of other organs hence outcome measures should include these different aspects of disease. Muscle strength and muscle endurance are the most specific clinical features that should be assessed during treatment and longitudinal follow-up. Extramuscular involvement should also be assessed. An international, interdisciplinary network, the International Myositis Assessment Clinical Study Group (IMACS) has proposed a core set of outcome measures to assess three dimensions of myositis disease; disease activity (MYOACT), disease damage (MYODAM) and health related quality of life (SF-36) to be used in clinical trials. These include scoring of extramuscular involvement (skin, lungs, articular, cardiac, gastro-intestinal tract) in both the disease activity and damage scores. In the disease activity score, muscle strength is measured by the manual muscle test (MMT)- 8, this could easily be used in clinical practice. Other myositis specific outcome measures are the Functional Index of myositis (FI) -- 2 to measure muscle endurance and a questionnaire, the Myo-sitis Activities Profile (MAP) to measure patient perspective. A close collaboration between physicians, physical and occupational therapists and specialized nurses is of great value in care and disease assessment of patients with polymyositis and dermatomyositis.

The safety of a resistive home exercise program in patients with recent onset active polymyositis or dermatomyositis.

The objective was to investigate whether a 12-week resistive home exercise program in addition to conventional medical treatment could be safely performed regarding muscle inflammation, muscle function, and quality of life in patients with active polymyositis (PM) or dermatomyositis (DM). Eleven patients diagnosed with active PM or DM were included. Muscle biopsies and Magnetic Resonance Imaging (MRI) of the thighs were performed. Quality of life, function, and subjective global disease impact (SGDI) were assessed and creatine phosphokinase levels (CPK) were analysed. The patients exercised with the exercise program for 15 minutes and took a 15-minute walk five days a week for 12 weeks. After the exercise period there was no sign of increased muscle inflammation. The group showed significantly improved function and quality of life compared to the start of study. It seems that this exercise program safely can be employed in patients with active PM or DM, and we suggest that physical exercise should be included in the rehabilitation of these patients.

Decreased expression of interleukin-1alpha, interleukin-1beta, and cell adhesion molecules in muscle tissue following corticosteroid treatment in patients with polymyositis and dermatomyositis.

OBJECTIVE: To study the effects of immunosuppressive therapy, in particular, corticosteroids, on morphologic signs of inflammation and expression of cytokines, adhesion molecules, and class I major histocompatibility complex (MHC) antigen in muscle tissue from patients with polymyositis (PM) and dermatomyositis (DM) and to correlate the molecular changes with changes in muscle function. METHODS: Seven patients with PM and 4 patients with DM underwent muscle biopsy before and after 3-6 months of therapy. Ten of the 11 patients were initially treated with prednisolone 30-60 mg/day. The phenotypes of infiltrating inflammatory cells and the expression of interleukin-1alpha (IL-1alpha) and IL-1beta, adhesion molecules, and class I MHC antigen were studied by immunochemistry. Computerized image analysis was used for quantitation of staining. Muscle function was assessed with a muscle function index score. RESULTS: Pronounced improvement of muscle function during the treatment period was noted in 8 of the 11 patients. The changes in muscle function coincided with an almost complete disappearance of inflammatory cells, including CD3+ T cells, in the patients with clinical improvement. These patients also exhibited decreased expression of IL-1alpha, IL-1beta, intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), leukocyte function-associated antigen 1alpha, and very late activation antigen 4alpha. Of note, there was persistent expression of IL-1alpha, ICAM-1, and VCAM-1 in capillaries and of class I MHC antigens on muscle fibers in several of the patients who, after corticosteroid treatment, still had muscle weakness despite the disappearance of inflammatory infiltrates. CONCLUSION: Changes in the muscle expression of key molecules in the inflammatory process, such as IL-1alpha and IL-1beta, ICAM-1 and class I MHC antigens, showed a consistent but not complete concordance with changes in and status of muscle function in patients with myositis who received the current standard treatment for the disease. These data indicate that it is possible to further evaluate various therapies for myositis using molecular analysis of muscle biopsy specimens obtained on repeated occasions. In addition, the data demonstrate a dissociation between muscle function and degree of inflammatory infiltration in the affected muscles and suggest that the functional defects are more related to the expression of molecules such as IL-1alpha in muscle capillaries than to the mere presence of inflammatory cells in the affected muscles.

Safety of a home exercise programme in patients with polymyositis and dermatomyositis: a pilot study.

OBJECTIVES: To investigate whether a home exercise programme could safely be performed by patients with stable, inactive polymyositis (PM) and dermatomyositis (DM), regarding disease activity, muscle function, health status and pain. METHODS: Ten patients with reduced muscle function completed the study. A home exercise programme including exercises for strength in the upper and lower limbs, neck and trunk, for mobility in the upper limbs and moderate stretching was developed. The patients exercised for 15 min and took a 15 min walk 5 days a week during a 12 week period. Assessments included clinical evaluation of disease activity, serum creatinine phosphokinase (CPK) levels, magnetic resonance imaging (MRI) of the quadriceps, repeated muscle biopsy of the vastus lateralis, a muscle function index (FI), a walking test and a health status instrument (the SF 36) performed at the start of the study and after 12 weeks. RESULTS: After 12 weeks of exercise, there were no signs of increased disease activity as assessed clinically, by CPK values, MRI or muscle biopsy findings. On an individual basis, all patients improved regarding muscle function according to the FI, in six cases the improvement reached statistical significance (P < 0.05). A significant improvement regarding muscle function in the upper and lower limbs, walking distance and general health status was achieved. CONCLUSIONS: Our results indicate that this home exercise programme can be safely employed in patients with stable, inactive PM and DM, with beneficial effects on muscle function.

Exercise and variations in neuropeptide concentrations in rheumatoid arthritis.

The aim of the present study was to investigate the influence of an exercise program on neuropeptide concentrations, disease activity, impairments and disabilities in rheumatoid arthritis (RA). Eleven females (median age 60 years, median disease duration 6.5 years, ARA functional classes I or II) exercised 30 min daily for 4 weeks. The urine concentrations of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) and neuropeptide Y-like immunoreactivity (NPY-LI) were analyzed 1 week prior to exercise start, at exercise start, after 2 and 4 weeks of exercise, and after a 4-week follow-up period. Measurements of disease activity, aerobic capacity, grip force, limb muscle function, and activities of daily living (ADL) were also undertaken. The results indicate a decrease (md 5.64 pM to md 3.48 pM, P