New paradigm in the treatment of myositis-associated interstitial lung disease.

INTRODUCTION: Interstitial lung disease (ILD) is the leading cause of mortality in idiopathic inflammatory myopathies or myositis. Clinical characteristics, including the course of ILD, rate of progression, radiological and pathohistological morphologies, extent and distribution of inflammation and fibrosis, responses to treatment, recurrence rate, and prognosis, are highly variable among myositis patients. A standard practice for ILD management in myositis patients has not yet been established. AREAS COVERED: Recent studies have demonstrated the stratification of patients with myositis-associated ILD into more homogeneous groups based on the disease behavior and myositis-specific autoantibody (MSA) profile, leading to better prognoses and prevention of the burden of organ damage. This review introduces a new paradigm in the management of myositis-associated ILD based on research findings from relevant literature selected by a search of PubMed as of January 2023, as well as expert opinions. EXPERT OPINION: Managing strategies for myositis-associated ILD are being established to stratify patients based on the severity of ILD and the prediction of prognosis based on the disease behavior and MSA profile. The development of a precision medicine treatment approach will provide benefits to all relevant communities.

Harnessing the benefits of yoga for myositis, muscle dystrophies, and other musculoskeletal disorders.

The recent global increase in popularity of home-based yoga, an ancient Indian technique practiced for thousands of years, has translated into its use as a complementary therapy for a multitude of ailments. This review aims to examine the published literature regarding the effects of yoga therapy on systemic chronic diseases; in particular on the inflammatory myopathies (IMs) and other muscle disorders.Despite the fact that the evidence base for yoga in inflammatory myositis is in its infancy, collateral results in other disorders such as muscular dystrophies are promising. A beneficial effect of yoga in chronic pain has been shown alongside an improvement in motor function and muscle strength. Patients with Duchenne muscular dystrophy with respiratory involvement may find improvement in lung function. Elderly patients may experience reduction in falls secondary to an improvement in balance while practicing long-term yoga therapy.Further benefits are improving disorders of mental health such as depression and anxiety. A reported improvement in overall quality of life further suggests its efficacy in reducing morbidity in patients with chronic diseases, who often suffer co-existent psychological comorbidities.

Risk Factors and Cancer Screening in Myositis.

The idiopathic inflammatory myopathies, particularly dermatomyositis, are associated with an increased risk of cancer. Lung, ovarian, breast, colon, prostate, and cervical cancers, and hematologic malignancies, are among the most common associated cancers. Risk stratification for cancer in patients with myositis is based on clinical risk factors/red flags, myositis clinical subtypes, and myositis-specific autoantibodies. Clinical risk factors include older age at disease onset, male gender, dysphagia, acute onset/refractory myositis, cutaneous ulceration, necrosis/vasculitis, and elevated inflammatory markers. Appropriate screening strategies are based on the risk level. Further studies are warranted to determine the role of advanced imaging and comprehensive cancer screening.

Long-term treatment with human immunoglobulin for antisynthetase syndrome-associated interstitial lung disease.

BACKGROUND: Interstitial lung disease-associated antisynthetase syndrome (AS-ILD) carries significant morbidity and mortality. Corticosteroids and immunosuppressive drugs are the mainstay of treatment. Human immunoglobulin (IVIg), an immunomodulator without immunosuppressive properties, is effective in myositis but the evidence supporting its use in ILD is scarce. OBJECTIVE: To describe clinical outcomes of AS-ILD patients receiving IVIg. METHODS: Retrospective analysis of AS-ILD patients. Linear mixed models using restricted maximum likelihood estimation was used to estimate the change in lung function and corticosteroid dose over time. RESULTS: Data from 17 patients was analyzed. Median follow-up was 24.6 months. Fourteen patients had refractory disease. The mean percent-predicted forced vital capacity (FVC%) (p = 0.048) and percent-predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (p = 0.0223) increased over time, while the mean prednisone dose (p < 0.001) decreased over time. Seven patients achieved a >10% increase in FVC%, including two who used IVIg as initial treatment. Five patients showed a >10% increase in DLCO% and TLC%. Nine (53%) patients experienced side effects. CONCLUSIONS: IVIg may be a useful complementary therapy in active progressive AS-ILD but is associated with potential side effects. Fssssurther investigation is required to determine the value of IVIg as an initial treatment in AS-ILD.

Increased risk of coronary heart disease among patients with idiopathic inflammatory myositis: a nationwide population study in Taiwan.

OBJECTIVE: To evaluate the risk of incident coronary heart disease (CHD) among patients with DM and PM in a general population context. METHODS: We conducted a retrospective cohort study using the Taiwan National Health Insurance Research Database containing records covering the years from 2000 to 2010. DM and PM were confined for the purposes of this study to those aged ⩾18 years who were eligible for the Taiwan catastrophic illness certificate. The diagnoses, CHD outcomes and cardiovascular risk factors were identified from electronic claims data. We conducted two cohort analyses: CHD and DM, and CHD and PM, excluding for each analysis individuals with CHD already identified at baseline. Data for the comparison group was obtained from the Longitudinal Health Insurance database, comprising 1 million persons randomly sampled from the total beneficiaries during 2000. We estimated hazard ratios comparing myositis with comparison cohorts, adjusting for potential cardiovascular risk factors. RESULTS: A total of 1145 patients with idiopathic myositis were identified, along with 732 723 control patients aged ⩾18 years. The incidence rates of CHD were 15.1 in DM and 30.1 in PM per 1000 person-years, vs 8.4 and 10.5 per 1000 person-years in the comparison cohort. The adjusted hazard ratios for CHD in patients with idiopathic myositis were 2.21 (95% CI 1.64, 2.99) for DM and 3.73 (95% CI 2.83, 4.90) for PM. CONCLUSION: Results of this general population-based cohort study suggest that DM and PM are associated with an increased risk of CHD.

Gastrointestinal and Hepatic Disease in the Inflammatory Myopathies.

Although muscle weakness is the pathognomonic feature of idiopathic inflammatory myopathies, systemic organ involvement is not uncommon. The gastrointestinal and hepatic manifestations are well known. Oropharyngeal dysphagia is the most common gastrointestinal symptom and can be severe. Gastric and small intestinal motility disorders, including chronic intestinal pseudo-obstruction, celiac disease, and inflammatory bowel disease have been described. Comprehensive cancer screening is warranted soon after the diagnosis of inflammatory myopathies due to high risk of occult malignancies. Elevated aminotransferases may suggest muscular injury rather than hepatic dysfunction. Knowledge regarding systemic involvement of inflammatory myopathies can assist in timely diagnosis of these complex disorders.

Gabapentin decreases microglial cells and reverses bilateral hyperalgesia and allodynia in rats with chronic myositis.

In the present work, we investigated the antinociceptive effect of gabapentin in a chronic myositis model and its interference in spinal glial cells. Chronic myositis was induced by injection of Complete Freund Adjuvant (CFA) into the right gastrocnemius (GS) muscle of rats and tests for evaluating mechanical hyperalgesia, thermal hyperalgesia and tactile allodynia were performed. Pharmacological treatment with gabapentin was administrated intrathecally and 100µg and 200µg doses were tested. For analyzing astrocytes and microglia in the spinal cord, immunochemistry assay was performed. It was found that gabapentin 200µg reverted CFA-induced chronic muscle pain bilaterally, in all applied tests and it was able to attenuate microglial but not astrocytes activation in the dorsal horn of spinal cord. In conclusion, gabapentin was able to inhibit hyperalgesia and allodynia in chronic myositis and also to attenuate spinal microglial activation. Therefore, gabapentin could be used as treatment for targeting chronic muscle pain.

[Musculoskeletal-related chest pain]. / Muskuloskeletal bedingter Thoraxschmerz.

BACKGROUND: Approximately 10-50% of chest pains are caused by musculoskeletal disorders. The association is twice as frequent in primary care as in emergency admissions. AIM: This article provides an overview of the most important musculoskeletal causes of chest pain and on the diagnostics and therapy. METHODS: A selective search and analysis of the literature related to the topic of musculoskeletal causes of chest pain were carried out. RESULTS AND CONCLUSION: Non-inflammatory diseases, such as costochondritis and fibromyalgia are frequent causes of chest pain. Inflammatory diseases, such as rheumatoid arthritis, spondyloarthritis and systemic lupus erythematosus are much less common but are more severe conditions and therefore have to be diagnosed and treated. The diagnostics and treatment often necessitate interdisciplinary approaches. Chest pain caused by musculoskeletal diseases always represents a diagnosis by exclusion of other severe diseases of the heart, lungs and stomach. Physiotherapeutic and physical treatment measures are particularly important, including manual therapy, transcutaneous electrical stimulation and stabilization exercises, especially for functional myofascial disorders.

Miotonía congénita, una miopatía no distrófica / Myotonia congenita, a non-dystrophic myopathy

La miotonía congénita es la forma más común de miotonía no distrófica. Esta miopatía está causada por mutaciones en el gen CLCN1, codificante del principal canal de iones cloruro del músculo esquelético (ClC-1); la alteración de la función de este canal, regulado por voltaje, da lugar al fenómeno de miotonía. La enfermedad se puede heredar con un tipo de herencia dominante (enfermedad de Thomsen) o recesiva (enfermedad de Becker o miotonía congénita generalizada). El fenotipo clínico de ambas formas de la enfermedad es similar aunque la forma recesiva se caracteriza por una mayor gravedad de los síntomas. El diagnóstico clínico de miotonía congénita debe sospecharse cuando encontramos en un paciente episodios de rigidez muscular (miotonía), remisión o alivio de la rigidez con el ejercicio (fenómeno warm-up), miotonía clínica, un patrón electromiográfico característico y/o historia familiar. El diagnóstico molecular de miotonía congénita consiste en el análisis por secuenciación del gen CLCN1 (AU)

Myotonia congenita is the most common form of non-dystrophic myotonia. This myopathy is caused by mutations in the CLCN1 gene, encoding the main skeletal muscle chloride ion channel (ClC-1). Altering the function of this voltage-gated channel, leads to the phenomenon of myotonia. The disease can be inherited with a dominant (Thomsen disease) or recessive type (Becker disease or congenital generalised myotonia). The clinical phenotype of both forms of the disease is similar, although the recessive form is characterised by more severe symptoms. The clinical diagnosis of congenital myotonia should be suspected in a patient who presents with episodes of muscle stiffness (myotonia), remission or relief from stiffness with exercise (warm-up phenomenon), and a characteristic electromyography pattern, and/or family history. Sequencing the CLCN1 gene is the present approach for molecular diagnosis of myotonia congenita (AU)

Life-Threatening Hypercalcemia Revealing Diffuse and Isolated Acute Sarcoid-Like Myositis: A New Entity? (A Case-Series).

Up to 50% patients with sarcoidosis display extra-pulmonary disease. However, initial and isolated (ie, without lung disease) acute muscular involvement associated with pseudo-malignant hypercalcemia is very uncommon. We report on 3 cases of life-threatening hypercalcemia revealing florid and isolated acute sarcoid-like myositis.All patients complained of fatigue, progressive general muscle weakness, and weight loss. Laboratory tests showed a severe life-threatening hypercalcemia (>3.4 mmol/L). Hypercalcemia was associated with increased serum level of 1,25-(OH)2 vitamin D and complicated with acute renal failure. One patient displayed acute pancreatitis due to hypercalcemia.In all cases, PET-scan, performed for malignancy screening, incidentally revealed an intense, diffuse, and isolated muscular fluorodeoxyglucose (FDG) uptake consistent with diffuse non-necrotizing giant cells granulomatous myositis demonstrated by muscle biopsy. Of note, creatine phosphokinase blood level was normal in all cases. No patients displayed the usual thoracic features of sarcoidosis.All patients were treated with high dose steroids and achieved rapid, complete, and sustained remission. A review of English and French publications in Medline revealed 5 similar published cases.Steroid-sensitive acute sarcoid-like myositis causing high calcitriol levels and life-threatening hypercalcemia should be recognized as a separate entity.

The role of TRPA1 in muscle pain and mechanical hypersensitivity under inflammatory conditions in rats.

Transient receptor potential cation channel, subfamily A, member 1 (TRPA1) is expressed in muscle afferents and direct activation of these receptors induces acute mechanical hypersensitivity. However, the functional role of TRPA1 under pathological muscle pain conditions and mechanisms by which TRPA1 mediate muscle pain and hyperalgesia are not clearly understood. Two rodent behavioral models validated to assess craniofacial muscle pain conditions were used to study ATP- and N-Methyl-D-aspartate (NMDA)-induced acute mechanical hypersensitivity and complete Freund's adjuvant (CFA)-induced persistent mechanical hypersensitivity. The rat grimace scale (RGS) was utilized to assess inflammation-induced spontaneous muscle pain. Behavioral pharmacology experiments were performed to assess the effects of AP18, a selective TRPA1 antagonist under these conditions. TRPA1 expression levels in trigeminal ganglia (TG) were examined before and after CFA treatment in the rat masseter muscle. Pre-treatment of the muscle with AP18 dose-dependently blocked the development of acute mechanical hypersensitivity induced by NMDA and α,ß-methylene adenosine triphosphate (αßmeATP), a specific agonist for NMDA and P2X3 receptor, respectively. CFA-induced mechanical hypersensitivity and spontaneous muscle pain responses were significantly reversed by post-treatment of the muscle with AP18 when CFA effects were most prominent. CFA-induced myositis was accompanied by significant up-regulation of TRPA1 expression in TG. Our findings showed that TRPA1 in muscle afferents plays an important role in the development of acute mechanical hypersensitivity and in the maintenance of persistent muscle pain and hypersensitivity. Our data suggested that TRPA1 may serve as a downstream target of pro-nociceptive ion channels, such as P2X3 and NMDA receptors in masseter afferents, and that increased TRPA1 expression under inflammatory conditions may contribute to the maintenance of persistent muscle pain and mechanical hyperalgesia. Mechanistic studies elucidating transcriptional or post-translational regulation of TRPA1 expression under pathological pain conditions should provide important basic information to further advance the treatment of craniofacial muscle pain conditions.

[Biological therapy in idiopathic inflammatory myopathies]. / Biológiai terápia idiopathiás inflammatorikus myopathiákban.

Idiopathic inflammatory myopathies are systemic, immune-mediated diseases characterized by proximal, symmetrical, progressive muscle weakness. The aim of this work is to give an overview of the biological therapy used in the treatment of idiopathic inflammatory myopathies. The authors also focus on novel results in the therapy directed against the B- and T-cells. They emphasize the importance of new trials in these diseases which may lead to the introduction of novel therapeutic options in these disorders.

Fractalkine signaling in microglia contributes to ectopic orofacial pain following trapezius muscle inflammation.

Fractalkine (FKN) signaling is involved in mechanical allodynia in the facial skin following trapezius muscle inflammation. Complete Freund's adjuvant (CFA) injection into the trapezius muscle produced mechanical allodynia in the ipsilateral facial skin that was not associated with facial skin inflammation and resulted in FKN but not FKN receptor (CX3CR1) expression, and microglial activation was enhanced in trigeminal spinal subnucleus caudalis (Vc) and upper cervical spinal cord (C1-C2). Intra-cisterna magna anti-CX3CR1 or anti-interleukin (IL)-1ß neutralizing antibody administration decreased the enhanced excitability of Vc and C1-C2 neurons in CFA-injected rats, whereas intra-cisterna magna FKN administration induced microglial activation and mechanical allodynia in the facial skin. IL-1ß expression and p38 mitogen-activated protein kinase phosphorylation were enhanced in activated microglia after CFA injection. The excitability of neurons whose receptive fields was located in the facial skin was significantly enhanced in CFA-injected rats, and the number of cells expressing phosphorylated extracellular signal-regulated kinase (pERK) following noxious mechanical stimulation of the facial skin was significantly increased in Vc and C1-C2. We also observed mechanical allodynia of the trapezius muscle as well as microglial activation and increased pERK expression in C2-C6 after noxious stimulation of the trapezius muscle in facial skin-inflamed rats. These findings suggest that FKN expression was enhanced in Vc and C1-C2 or C2-C6 following trapezius muscle or facial skin inflammation, microglia are activated via FKN signaling, IL-1ß is released from the activated microglia, and the excitability of neurons in Vc and C1-C2 or C2-C6 is enhanced, resulting in the ectopic mechanical allodynia.

A case of severe 1,25-dihydroxyvitamin D-mediated hypercalcemia due to a granulomatous disorder.

BACKGROUND: Profound hypercalcemia is usually due to underlying malignancy. CASE: We describe a case of granulomatous myositis presenting with extreme hypercalcemia of 20.1 mg/dl and generalized weakness that did not resolve despite rapid correction of serum calcium. The disease process was unmasked by cholecalciferol supplementation. Initial search for a malignant process yielded no diagnosis, but an elevated 1,25-dihydroxyvitamin D level, in the setting of a suppressed PTH and undetectable PTHrP, pointed to the presence of excessive 1α-hydroxylase activity. METHODS AND RESULTS: Biopsy of the vastus lateralis muscle showed extensive granulomatous myositis. Immunohistochemical staining for 1α-hydroxylase was localized to the multinucleated giant cells and histiocytes. Musculoskeletal magnetic resonance imaging showed involvement of proximal muscle groups of both thighs and upper limbs. CONCLUSION: Measurement of vitamin D metabolites is pivotal in diagnosing 1,25-dihydroxyvitamin D-mediated hypercalcemia. Granulomatous disease can occasionally cause profound hypercalcemia and needs to be considered in the differential diagnosis. 1,25-Dihydroxyvitamin D-mediated hypercalcemia is responsive to glucocorticoid therapy.

Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency leading to statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.

Myositis-myalgia is the most common cause of statin intolerance, leading to cessation of statin use, with consequent failure to lower LDL cholesterol to target levels for primary and secondary prevention of cardiovascular disease (CVD). We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent 25 (OH) vitamin D deficiency and statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle. In hypercholesterolemic, vitamin D deficient patients, intolerant to statins because of myositis-myalgia, three non-blinded clinical case series have uniformly demonstrated that after supplementation with oral vitamin D2 which normalizes serum 25 (OH) vitamin D levels, statins can be successfully re-instituted in >90% of patients, without recurrent myositis-myalgia, with reduction of LDL cholesterol to target levels. Empirically, in 68 hypercholesterolemic patients, unable to tolerate≥1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we have prospectively assessed whether resolution of vitamin D deficiency would result in statin tolerance, free of myositis-myalgia. On no statins, 50,000 units of vitamin D2 was given twice/week for 3 weeks, and was then continued once/week. After 3 weeks on vitamin D supplementation, statins were restarted, and patients were re-assessed after 3 months on statins while continuing vitamin D supplementation. At 3 months follow-up, on vitamin D supplementation and re-instituted statins, 62 of 68 (91%) previously statin-intolerant patients now tolerated statins well and were asymptomatic without myositis-myalgia. In these 68 patients, on vitamin D supplementation and statins, mean±SD vitamin D rose from 22±7 to 43±13 ng/ml (p<0.0001), and LDL cholesterol fell from 162±55 to 101±35 mg/dl (p<0.0001). Despite published and new empirical evidence, the medical establishment has refused to accept the hypothesis, requiring placebo-controlled, double-blind studies, none having been reported to date. A placebo-controlled, double-blind study is needed to document that normalization of serum 25 (OH) vitamin D levels in vitamin D deficient, statin intolerant patients would facilitate re-introduction of statins with concurrent freedom from myositis-myalgia. The ability to reverse myositis-myalgia in vitamin D deficient, statin intolerant, hypercholesterolemic patients by vitamin D supplementation would be extraordinarily valuable, facilitating reinstitution of statins to lower LDL cholesterol to reduce risk of CVD events. We hypothesize that symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent vitamin D deficiency producing statin intolerance may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle.

Vitamin D deficiency, myositis-myalgia, and reversible statin intolerance.

OBJECTIVE: In 150 hypercholesterolemic patients, unable to tolerate ≥1 statin because of myositis-myalgia, selected by low (<32 ng/ml) serum 25 (OH) vitamin D, we prospectively assessed whether vitamin D supplementation with resolution of vitamin D deficiency would result in statin tolerance, free of myositis-myalgia. RESEARCH DESIGN AND METHODS: We studied 74 men, 76 women, median age 60, 131 white, 17 black and 2 other. On no statins, 50,000 units of vitamin D was given twice a week for 3 weeks, and then continued once a week. After 3 weeks on vitamin D, statins were restarted. Patients were re-assessed on statins and vitamin D every 3 to 4 months, with serial measures of serum 25 (OH) vitamin D, creatine phosphokinase (CPK), LDL cholesterol (LDLC) and assessment of myositis-myalgia. MAIN OUTCOME MEASURES: Percentage of patients myalgia-free on vitamin D plus reinstituted statins, serum 25 (OH) vitamin D, CPK, and LDLC on reinstituted statins and concurrent vitamin D supplementation. RESULTS: On vitamin D supplementation plus re-instituted statins for a median of 8.1 months, 131 of the 150 patients (87%) were free of myositis-myalgia and tolerated the statins well. Serum 25 (OH) vitamin D increased from median 21 to 40 ng/ml (p < 0.001), and normalized (≥32 ng/ml) in 117 (78%) of 150 previously vitamin D deficient, statin-intolerant patients. Median LDLC decreased from 146 mg/dl to 95 mg/dl, p < 0.001. CONCLUSION: Symptomatic myositis-myalgia in hypercholesterolemic statin-treated patients with concurrent serum 25 (OH) vitamin D deficiency may reflect a reversible interaction between vitamin D deficiency and statins on skeletal muscle causing myalgia.