Muscle Enzymes Research Articles

Autoantigenic properties of the aminoacyl tRNA synthetase family in idiopathic inflammatory myopathies

ObjectivesAutoantibodies are thought to play a key role in the pathogenesis of idiopathic inflammatory myopathies (IIM). However, up to 40% of IIM patients, even those with clinical manifestations of anti-synthetase syndrome (ASSD), test seronegative to known myositis-specific autoantibodies. We hypothesized the existence of new potential autoantigens among human cytoplasmic aminoacyl tRNA synthetases (aaRS) in patients with IIM. MethodsPlasma samples from 217 patients with IIM according to 2017 EULAR/ACR criteria, including 50 patients with ASSD, 165 without, and two with unknown ASSD status were identified retrospectively, as well as age and gender-matched sera from 156 population controls, and 219 disease controls. Patients with previously documented ASSD had to test positive for at least one of the five most common anti-aaRS autoantibodies (anti-Jo1, -PL7, -PL12, -EJ, and -OJ) and present with one or more of the following clinical manifestations: interstitial lung disease, myositis, arthritis, Raynaud's phenomenon, fever, or mechanic's hands. Demographics, laboratory, and clinical data of the IIM cohort (ASSD and non-ASSD) were compared. Samples were screened using a multiplex bead array assay for presence of autoantibodies against a panel of 117 recombinant protein variants, representing 33 myositis-related proteins, including all nineteen cytoplasmic aaRS. Prospectively collected clinical data for the IIM cohort were retrieved and compared between groups within the IIM cohort and correlated with the results of the autoantibody screening. Principal component analysis was used to analyze clinical manifestations between ASSD, non-ASSD groups, and individuals with novel anti-aaRS autoantibodies. ResultsWe identified reactivity towards 16 aaRS in 72 of the 217 IIM patients. Twelve patients displayed reactivity against nine novel aaRS. The novel autoantibody specificities were detected in four previously seronegative patients for myositis-specific autoantibodies and eight with previously detected myositis-specific autoantibodies. IIM individuals with novel anti-aaRS autoantibodies (n = 12) all had signs of myositis, and they had either muscle weakness and/or muscle enzyme elevation, 2/12 had mechanic's hands, 3/12 had interstitial lung disease, and 2/12 had arthritis. The individuals with novel anti-aaRS and a pathological muscle biopsy all presented widespread up-regulation of major histocompatibility complex class I. The reactivities against novel aaRS could be confirmed in ELISA and western blot. Using the multiplex bead array assay, we could confirm previously known reactivities to four of the most common aaRS (Jo1, PL12, PL7, and EJ (n = 45)) and identified patients positive for anti-Zo, -KS, and -HA (n = 10) that were not previously tested. A low frequency of anti-aaRS autoantibodies was also detected in controls. ConclusionOur results suggest that most, if not all, cytoplasmic aaRS may become autoantigenic. Autoantibodies against new aaRS may be found in plasma of patients previously classified as seronegative with potential high clinical relevance.

Assessment of idiopathic inflammatory myopathy using a deep learning method for muscle T2 mapping segmentation

ObjectiveTo investigate the utility of an automatic deep learning (DL) method for segmentation of T2 maps in patients with idiopathic inflammatory myopathy (IIM) against healthy controls, and also the association of quantitative T2 values in patients with laboratory and pulmonary findings.MethodsStructural MRI and T2 mapping of bilateral thigh muscles from patients with IIM and healthy volunteers were segmented using dedicated software based on a pre-trained convolutional neural network. Incremental and federated learning were implemented for continuous adaptation and improvement. Muscle T2 values derived from DL segmentation were compared between patients and healthy controls, and T2 values of patients were further analyzed with serum muscle enzymes, and interstitial lung disease (ILD) which was diagnosed and graded based on chest HRCT.ResultsOverall, 64 patients (27 patients with dermatomyositis, 29 with polymyositis, and 8 with antisynthetase syndrome (ASS)) and 10 healthy controls were included. By using DL-based muscle segmentation, T2 values generated from T2 maps accurately differentiated patients from those of controls (p < 0.001) with a cutoff value of 36.4 ms (sensitivity 96.9%, and specificity 100%). In patients with IIM, muscle T2 values positively correlated with all the serum muscle enzymes (all p < 0.05). ILD score of patients with ASS was markedly higher than that of those without ASS (p = 0.011), while dissociation between the severity of muscular involvement and ILD was observed (p = 0.080).ConclusionAutomatic DL could be used to segment thigh muscles and help quantitatively assess muscular inflammation of IIM through T2 mapping.Key Points• Muscle T2 mapping automatically segmented by deep learning can differentiate IIM from healthy controls.• T2 value, an indicator of active muscle inflammation, positively correlates with serum muscle enzymes.• T2 mapping can detect muscle disease in patients with normal muscle enzyme levels.

Peripheral neuropathy caused by fenugreek (Trigonella foenum-graecum) straw intoxication in cattle and experimental reproduction in sheep and goats.

Trigonella foenum-graecum (fenugreek) is a legume widely used as a food supplement in humans and less frequently in ruminants. Toxicity has been described sporadically in ruminants grazing mature fenugreek plants or stubble; however, the pathological features are unclear. This report describes a natural outbreak of intoxication in cattle fed fenugreek straw and the experimental reproduction using 8 sheep and 8 goats. Affected cattle presented clinical signs approximately 1 month after consuming the straw and 100 of 400 cattle (25%) were affected, of which 60 of 100 (60%) died or were euthanized. Clinical signs were characterized by proprioceptive positioning defects with abnormal postures and weakness of hindlimbs. Forelimbs were also affected in severely affected animals, and cattle became recumbent. Locomotion was characterized by trembling, and some cattle showed high-stepping movements of their forelimbs and knuckled over in their fetlocks. Experimental intoxication induced clinical signs only in sheep and were similar to cattle, although with signs starting in the forelegs. Gross and microscopic lesions were similar in spontaneous and experimental intoxications. Macroscopic changes corresponded with muscular hemorrhages and edema, mainly surrounding the peripheral nerves. Microscopic examination only demonstrated lesions in the distal peripheral nerves, which included edema, hemorrhages, and Wallerian degeneration. Neurofilament immunohistochemistry revealed altered axon labeling and S100 showed a decrease in myelin intensity and loss of its typical compact arrangement around axons. Biochemical and hematological abnormalities included elevated levels of muscle and liver enzymes and thrombocytopenia. These findings indicate that fenugreek straw induces peripheral neuropathy in cattle and sheep, but not in goats.

A Rare Case Of Hoffman Syndrome Presented As Hypothyroid Myopathy

Hypothyroidism's neurological manifestations are uncommon as first symptoms, and they usually appear later in the disease's course.Muscle hypertrophy is a very uncommon occurrence in hypothyroid people 1. Hoffmann's syndrome is a kind of hypothyroidism thatmanifests as muscle stiffness and pseudohypertrophy in adults. In most cases of hypothyroid myopathy, laboratory tests reveal elevatedlevels of muscle enzyme. The electro physiological investigation may reveal signs that indicate myopathy, neuropathy, or a combinedpattern of myopathy and neuropathy. Hormone replacement therapy 7 restores symptoms and normalises enzyme levels in the blood.Now, presenting a case of young age male presenting with hypothyroidism having features of calf muscle hypertrtrophy

Long-Term Efficacy and Safety of Evinacumab in Patients with Homozygous Familial Hypercholesterolemia: Real-World Clinical Experience.

Homozygous familial hypercholesterolemia (HoFH) is a rare, genetic condition characterized by markedly elevated plasma low-density lipoprotein cholesterol (LDL-C) concentrations from birth and increased risk of premature atherosclerotic cardiovascular disease. Evinacumab is an inhibitor of angiopoietin-like 3 protein that offers a new approach for correcting high LDL-C in HoFH. Evinacumab was administered intravenously (15 mg/kg Q4W) for 24 months in 7 patients with genetically confirmed HoFH, receiving background lipoprotein apheresis (LA) and/or lipid-lowering treatment (LLT). Assessment of efficacy and safety were carried out before and after 24 months of evinacumab treatment. The LDL-C lowering effect of evinacumab without LA were also investigated in the 7 HoFH patients after a subsequent compassionate extension period. Twenty-four months of treatment with evinacumab against background LA and LLT resulted in a significant reduction in LDL-C (-46.8%; p &lt; 0.001). LDL-C reduction with evinacumab was maintained during the compassionate extensions period in the absence of treatment with LA (-43.4%; mean follow-up of 208 ± 90 days). Evinacumab was well-tolerated, with no major adverse event reported or significant changes in liver and muscle enzyme concentrations. Our findings suggest that evinacumab is a safe and effective treatment for patients with HoFH receiving best standard of care in a routine setting.

Melanoma differentiation-associated gene 5 amyopathic dermatomyositis following an acute Mycoplasma pneumoniae infection: a case report

BackgroundA previously healthy young male of Southeast Asian descent presented with 6 weeks of fevers, cough, mucocutaneous ulcers, arthritis, and myalgias. Initial workup revealed positive Mycoplasma pneumoniae immunoglobulin M, and the patient was treated with antibiotics without relief of symptoms. Rheumatologic workup revealed highly positive melanoma differentiation-associated gene 5 antibody. Viral infections are thought to potentially trigger loss of self tolerance, and prompt the autoimmunity cascade that can result in conditions such as dermatomyositis. To our knowledge, this is the first case report demonstrating a non-viral infection, specifically Mycoplasma pneumoniae, as the inciting infectious trigger for the anti-melanoma differentiation-associated gene 5 dermatomyositis subtype.Case presentationA 20-year-old southeast Asian–American male with no significant past medical history presented with symptoms of intermittent fevers, nonproductive cough, dry eyes, oral ulcers, rash, arthritis, and myalgias. The patient was noted to have erythematous papules across the bilateral hands along the lateral digits and palms, as well as synovitis involving the bilateral hands and feet. Immunoglobulin M antibodies were positive for Mycoplasma pneumoniae. The patient was diagnosed with mycoplasma pneumonia. The patient did not respond to a course of antibiotics, leading to rheumatological testing that found highly positive melanoma differentiation-associated gene 5 autoantibody. Muscle enzyme and electromyography testing were normal, indicating clinically amyopathic disease. Methylprednisolone was initiated, with resolution of fevers and improvement of arthritis and myalgias. The cutaneous lesions on the digits and palms improved.ConclusionsThis patient presented with symptoms of fever, cough, oral ulcers, rashes, and arthritis, and blood work demonstrated the presence of immunoglobulin M antibodies to Mycoplasma pneumoniae. Despite antibiotic treatment for the presumed diagnosis of Mycoplasma pneumoniae infection, the patient did not improve, prompting rheumatological workup and revealing melanoma differentiation-associated gene 5 autoantibodies. This case suggests that infections, other than viral, can trigger the autoinflammatory cascade, leading to the development of amyopathic melanoma differentiation-associated gene 5 dermatomyositis.

ODP513 Rhabdomyolysis: A Rare Presentation Of Central hypothyroidism

Abstract Background Hypothyroidism is one of the most common endocrine disorders affecting approximately 5 percent of Americans aged 12 and older. The most common cause of hypothyroidism globally is iodine deficiency whereas in the United States, Hashimoto's thyroiditis is the most prevalent. Less frequently, hypothyroidism can be caused by central hypothyroidism. In uncontrolled states, this entity can lead to an array of complications with rhabdomyolysis being among the latest manifestations. We present a case when the patient was admitted to the hospital for significant rhabdomyolysis, and after workup, was found to be related to new onset central hypothyroidism. Clinical Case A 34-year-old African American male presented to our facility with proximal muscle weakness and pain in the bilateral hips and right shoulder for three days. During the interview, the patient was acutely debilitated demonstrating slow body movements and grimaces on passive and active range of motion. Motor strength and sensation was preserved in bilateral extremities. The patient denied any recent injury, compression, extensive exercise, seizure, or durg use. The patient, however, reported a family history of rheumatological and endocrine conditions. Labs were obtained and revealed a creatinine kinase level of 10,5000 U/L; creatinine kinase- MB 53.5 ng/mL; creatinine 1. 0 mg/dL; AST 146 U/L; ALT 72 U/L; CRP 8.6 mg/L. The patient was stabilized with appropriate fluid and steroid therapy. On further investigation, TSH and T4 levels were 0.30 µlU/mL and 0.55 ng/dL, respectively. MRI with and without contrast did not show any intracranial pituitary abnormality or mass. The patient was started on levothyroxine and instructed to remain on the drug as an outpatient to prevent future occurrences. He was subsequently discharged after CK levels normalized and proximal muscle weakness improved. The patient was instructed to have a repeat thyroid function test and T4 levels in 6 weeks with appropriate follow up. Conclusion Idiopathic central hypothyroidism is a rare cause of hypothyroidism estimated to occur in 1: 20,000-80,000 in the general public. The lack of a pituitary mass lesion on MRI added to the rarity of this presentation. Hypothyroid myopathy causing rhabdomyolysis is a known but rare consequence of untreated hypothyroidism, which may present with muscle weakness, pain, and elevated serum muscle enzyme. Prompt workup to rule out a multitude of other causes is required, and the patient should be closely monitored for electrolyte and kidney function changes. Levothyroxine remains the treatment of choice for correction of central hypothyroidism with dose adjustments based on patient symptoms and serum free T4 values. Presentation: No date and time listed

BKCa Activator NS1619 Improves the Structure and Function of Skeletal Muscle Mitochondria in Duchenne Dystrophy.

Duchenne muscular dystrophy (DMD) is a progressive hereditary disease caused by the absence of the dystrophin protein. This is secondarily accompanied by a dysregulation of ion homeostasis, in which mitochondria play an important role. In the present work, we show that mitochondrial dysfunction in the skeletal muscles of dystrophin-deficient mdx mice is accompanied by a reduction in K+ transport and a decrease in its content in the matrix. This is associated with a decrease in the expression of the mitochondrial large-conductance calcium-activated potassium channel (mitoBKCa) in the muscles of mdx mice, which play an important role in cytoprotection. We observed that the BKCa activator NS1619 caused a normalization of mitoBKCa expression and potassium homeostasis in the muscle mitochondria of these animals, which was accompanied by an increase in the calcium retention capacity, mitigation of oxidative stress, and improvement in mitochondrial ultrastructure. This effect of NS1619 contributed to the reduction of degeneration/regeneration cycles and fibrosis in the skeletal muscles of mdx mice as well as a normalization of sarcomere size, but had no effect on the leakage of muscle enzymes and muscle strength loss. In the case of wild-type mice, we noted the negative effect of NS1619 manifested in the inhibition of the functional activity of mitochondria and disruption of their structure, which, however, did not significantly affect the state of the skeletal muscles of the animals. This article discusses the role of mitoBKCa in the development of DMD and the prospects of the approach associated with the correction of its function in treatments of this secondary channelopathy.

An interesting case of dermatomyositis with classical presentation

Dermatomyositis, a connective tissue disorder, is an idiopathic inflammatory myopathy characterised by skin manifestation. The diagnosis of dermatomyositis is based on rashes on the skin, progressive muscle weakness, elevated serum muscle enzymes, abnormal electromyogram, and abnormal findings on muscle biopsy. Hereby presenting this rare case of a 57-year-old female with dermatomyositis with all the typical clinical findings with interstitial lung disease.

Impaired muscle strength is associated with ultrastructure damage in myositis

The muscle fiber ultrastructure in Idiopathic Inflammatory Myopathies (IIM) has been scarcely explored, especially in Inclusion Body Myositis. The aim of this study was to implement the Scanning Electron Microscopy (SEM) in a small cohort of IIM patients, together with the characterization of immunological profile for a better understanding of the pathophysiology. For immunological profile characterization, we identified the presence of autoantibodies (Ro-52, OJ, EJ, PL7, PL12, SRP, Jo-1, PMScl75, PMScl100, Ku, SAE1, NXP2, MDA5, TIF1γ, Mi-2α, Mi-2β) and quantified cytokines (IL-1β, IFN-α2, IFN-γ, TNF-α, IL-6, IL-10, IL-12p70, IL-17A, IL-18, IL-23, IL-33) and chemokines (CCL2, CXCL8). The histological analysis was made by hematoxylin–eosin staining while the muscle fiber ultrastructure was characterized by SEM. We observed changes in the morphology and structure of the muscle fiber according to muscle strength and muscle enzymes. We were able to find and describe muscle fiber ultrastructure with marked irregularities, porosities, disruption in the linearity and integrity of the fascicle, more evident in patients with increased serum levels of muscle enzymes and diminished muscle strength. Despite the scarce reports about the use of SEM as a tool in all clinical phenotypes of IIM, our work provides an excellent opportunity to discuss and reframe the clinical usefulness of SEM in the diagnostic approach of IIM.

46 Universal calcinosis in juvenile dermatomyositis: a case report

BackgroundDermatomyositis (DM) is an inflammatory myopathy that is often severe and affects children (juvenile DM) in 50% of cases. Subcutaneous calcinosis is seen in 30–70% of juvenile DM and often poses a problem in terms of treatment.We report a patient with diffuse subcutaneous calcinosis in juvenile DM.ObservationThe patient is K.S, a 17-year-old girl, with background history of congenital heart disease (atrial septal defect), which was corrected surgically in 2021. Since the age of 13, she has had DM for which she has received corticosteroid therapy at a dose of 2 mg/kg/day and improved clinically. The clinical examination reveals subcutaneous nodules in the arms, forearms, phalanx of the right index finger, inner thigh, knees and legs, associated with reduced range of movement of the right elbow (presence of calcifications) and limitation of internal rotation of the right hip.Laboratory investigations showed no inflammatory syndrome, the muscle enzymes and electromyogram were normal. Radiographs showed calcifications at the sites with subcutaneous nodules.Bone densitometry showed a decrease in bone mineral density (Z score= -3.4 standard deviation at the lumbar spine). The thoracic CT scan showed interstitial lung disease.The patient was managed with pamidronic acid for the diffuse calcinosis. She is also on diltiazem for Raynaud's phenomenon and hydroxychloroquine.ConclusionSubcutaneous calcinosis is diffuse in our patient. Treatment with bisphosphonates (pamidronic acid) is recommended.

48 Juvenile dermatomyositis: the experience of Military Pediatrics Department of Tunis

BackgroundJuvenile dermatomyositis (JD) is a rare autoimmune disorder characterized by a non-infectious inflammatory state affecting of the muscles and skin associated with a vasculopathy which represents the essential of its physiopathogenesis.ObjectivesTo review the clinical and biological diagnosis of DMJ as well as its evolution under treatment based on the cases of two patients at the Military Pediatrics Department of Tunis.ObservationsCase 1: This was a three-and-a-half-year-old child with a history of a simple febrile seizure, admitted for a skin rash and myalgia that had been evolving for eight months. Skin examination revealed an erythematous rash of the face and upper eyelids with erythematous papular lesions in front of the proximal interphalangeal joint recalling Gottron's papules. Muscle testing was in favor of a proximal deficiency and the electromyogram (EMG) revealed a diffuse myogenic process more pronounced on the proximal muscles without signs of myositic activity. Biology analysis did not reveal a biological inflammatory syndrome but rather increased muscle enzymes levels up to 3- and 4-times normal values. On the immune status report, there was no evidence of DMJ-specific autoantibodies (ASM), but the anti-SRP antibodies associated with myositis were present. The diagnosis of DMJ was established in view of the association of typical cutaneous signs and 3 muscular signs (proximal deficit, elevation of muscle enzymes, myogenic tracing) and an evaluation of the activity of the disease according to a standardized scale by the Childhood Myositis Assessment Scale (CMAS) was required (which was at 7/52). Treatment with corticosteroids and methotrexate was started after a pretherapeutic evaluation and regular check-ups of the child showed a clear improvement of clinical and muscular signs (CMAS became at 41/52). Case 2: A 7-year-old boy, with no previous pathological history, admitted to our department to explore his gait disorder associated to erythematosquamous lesions. At the dermatological inspection, a localized erythema was noted on the upper eyelids, the nose, the cheeks and the chin area, as well as erythematosquamous lesions on the interphalangeal joints, metacarpophalangeal joints, elbows and knees (Gottron papules). The gait was waddling, the EMG was in favor of myogenic disorder and the muscular testing revealed a proximal muscular affection. The biology results showed an elevation of CPK and LDH to 1.5 times the normal values and a sedimentation rate at 40 mm/h. The antibodies determination showed the existence of anti-NXP2 antibodies specific to myositis. The progression under treatment (corticosteroids, methotrexate and adjuvant treatment) was favorable with a CMAS score of 39 (CMAS was 11 when admitted). The persistence of squamous lesions recalling calcinosis on the dorsal surfaces of the forearms was well correlated with the presence of anti-NXP2 antibodies.ConclusionThe positive diagnosis of DMJ in a child must be based on clinical and biological arguments. The immunological characterization of DMJ should be an important element in the disease management because it can explain the lesions associated with certain myositis specific antibodies as well as their evolution, which implies a particular follow-up depending on the detected antibodies (risk of cancer in anti-NXP2 AC positive patients)

S3283 A Tough Pill to Swallow: A Case Series of Statin-Induced Necrotizing Autoimmune Myopathy Manifesting as Dysphagia and Transaminitis

Introduction: Statins are commonly used to prevent cardiovascular disease. However, a small subset of patients may develop autoimmune myopathy, a form of inflammatory myositis characterized by proximal muscle weakness and in some cases, dysphagia. We present two cases highlighting statin-induced necrotizing autoimmune myopathy (SINAM), a rare entity affecting roughly 2 cases per 1 million people. Case Description/Methods: Two Hispanic men, aged 60 and 71, presented with dysphagia and transaminitis. They reported gradual onset of proximal muscle weakness and weight loss and were taking atorvastatin 20mg and 80mg, respectively. Case 1: Labs revealed ALP 58 IU/L, AST 238 U/L, ALT 407 U/L, CK 7228 U/L, normal CRP, ESR, and HMG CoA reductase (HMGCR) antibodies 257 U/mL. EGD was unrevealing. MRI of the pelvis/femur showed patchy, symmetric intramuscular edema in leg muscles (Figure 1). Muscle biopsy revealed myonecrosis consistent with immune-mediated necrotizing myopathy. Case 2: Labs revealed ALP 79 IU/L, AST 571 U/L, ALT 373 U/L, CK 8392 U/L, CRP 19.2 mg/L, ESR 67 mm/hr, and HMGCR antibodies 367 U/mL. Muscle biopsy was not pursued. Both cases revealed negative viral hepatitis, ANA, myositis panel, smooth muscle Ab, LKM-1 Ab, total IgG, ferritin, anti-mitochondrial Ab, and alpha-1 antitrypsin. Both patients were started on high-dose steroids. Case 1 patient had minimal improvement and was subsequently started on mycophenolate and rituximab. He remains under close monitoring. Case 2 patient had persistent severe weakness and dysphagia, therefore intravenous immunoglobulin (IVIG) and mycophenolate were added. However, dysphagia persists despite a consistent decrease in muscle enzymes. He remains hospitalized and is pending PEG tube placement. (Figure) Discussion: SINAM is a rare variant of idiopathic inflammatory myopathy characterized by proximal muscle weakness and myofiber necrosis after statin exposure. Diagnosis is made with positive antibodies to HMGCR and may avoid the need for muscle biopsy in the appropriate clinical context. Cessation of statin and initiation of glucocorticoids are first-line treatments. However, many cases are refractory to steroid monotherapy. Other therapies such as IVIG and immunosuppressants serve a role in refractory disease. Alternative lipid-lowering agents should be used, and statins must not be rechallenged. These cases emphasize that muscle weakness, dysphagia and transaminitis should be evaluated diligently as early recognition can lead to initiation of life-saving treatment.Figure 1.: A-D. MRI pelvis/femur showing bilateral patchy and symmetric intramuscular edema in leg muscles.

INTERSTITIAL LUNG DISEASE IN A TODDLER WITH ANTI-MDA5 JUVENILE DERMATOMYOSITIS THAT IMPROVED WITH AGGRESSIVE, EARLY TREATMENT WITH STEROIDS AND MULTIPLE IMMUNOSUPPRESSANTS

INTERSTITIAL LUNG DISEASE IN A TODDLER WITH ANTI-MDA5 JUVENILE DERMATOMYOSITIS THAT IMPROVED WITH AGGRESSIVE, EARLY TREATMENT WITH STEROIDS AND MULTIPLE IMMUNOSUPPRESSANTS

Clinical analysis of the serum muscle enzyme spectrum of patients with newly diagnosed Sheehan's syndrome.

We investigated the factors associated with serum muscle enzyme elevation in patients with Sheehan’s syndrome. A total of 48 patients who were newly diagnosed with Sheehan’s syndrome were included and divided into 3 groups: Group 1, creatine kinase (CK) ≥ 1000 U/L; Group 2, 140 < CK < 1000 U/L; and Group 3, CK ≤ 140 U/L. Differences in serum muscle enzymes, serum electrolytes, blood glucose and hormones were compared among the 3 groups. A Spearman correlation analysis and multiple linear regression analysis were performed on serum muscle enzymes and the other variables. Four patients in Group 1 underwent electromyography. Fourteen, 26 and 8 patients were divided into Group 1, Group 2, and Group 3, respectively. The levels of plasma osmolality, serum sodium, free triiodothyronine (FT3) and free thyroxine (FT4) in Group 1 were lower than those in Group 3 at admission (P < .05). There were significant differences in CK, CK-MB, aspartate aminotransferase, lactate dehydrogenase, and alpha-hydroxybutyrate dehydrogenase among the three groups (P < .05). CK was correlated with serum sodium (r = −0.642, P < .001), serum potassium (r = −0.29, P = .046), plasma osmolality (r = −0.65, P < .001), FT3 (r = −0.363, P = .012), and FT4 (r = −0.450, P = .002). Moreover, creatine kinase isoenzyme-MB (CK-MB) was correlated with serum sodium (r = −0.464, P = .001) and plasma osmolality (r = −0.483, P < .001). The multiple linear regression showed that serum sodium was independently and negatively correlated with CK (r = −0.352, P = .021). The electromyogram results supported the existence of myogenic injury. Sheehan’s syndrome is prone to be complicated by nontraumatic rhabdomyolysis, with both a chronic course and acute exacerbation. Serum muscle enzymes should be routinely measured. For patients with CK levels > 1000 U/L, a CK-MB/CK ratio < 6% can be a simple indicator to differentiate rhabdomyolysis from acute myocardial infarction. Abnormal serum muscle enzymes observed in Sheehan’s syndrome may be associated with hypothyroidism and with hyponatremia in particular.

Glucose 6-P Dehydrogenase-An Antioxidant Enzyme with Regulatory Functions in Skeletal Muscle during Exercise.

Hypomorphic Glucose 6-P dehydrogenase (G6PD) alleles, which cause G6PD deficiency, affect around one in twenty people worldwide. The high incidence of G6PD deficiency may reflect an evolutionary adaptation to the widespread prevalence of malaria, as G6PD-deficient red blood cells (RBCs) are hostile to the malaria parasites that infect humans. Although medical interest in this enzyme deficiency has been mainly focused on RBCs, more recent evidence suggests that there are broader implications for G6PD deficiency in health, including in skeletal muscle diseases. G6PD catalyzes the rate-limiting step in the pentose phosphate pathway (PPP), which provides the precursors of nucleotide synthesis for DNA replication as well as reduced nicotinamide adenine dinucleotide phosphate (NADPH). NADPH is involved in the detoxification of cellular reactive oxygen species (ROS) and de novo lipid synthesis. An association between increased PPP activity and the stimulation of cell growth has been reported in different tissues including the skeletal muscle, liver, and kidney. PPP activity is increased in skeletal muscle during embryogenesis, denervation, ischemia, mechanical overload, the injection of myonecrotic agents, and physical exercise. In fact, the highest relative increase in the activity of skeletal muscle enzymes after one bout of exhaustive exercise is that of G6PD, suggesting that the activation of the PPP occurs in skeletal muscle to provide substrates for muscle repair. The age-associated loss in muscle mass and strength leads to a decrease in G6PD activity and protein content in skeletal muscle. G6PD overexpression in Drosophila Melanogaster and mice protects against metabolic stress, oxidative damage, and age-associated functional decline, and results in an extended median lifespan. This review discusses whether the well-known positive effects of exercise training in skeletal muscle are mediated through an increase in G6PD.

P42 Primary Sjogren’s Syndrome (pSS) in a seronegative adolescent female with family history of BehÇet’s disease: A challenging disease to diagnose Case-based discussion

Introduction/BackgroundSjogren’s Syndrome (SS) is heterogenous chronic autoimmune disease with symptoms ranging from organ-specific to variable non-specific systemic features. It is a rare disease in childhood and can be very difficult to diagnose, especially in seronegative patients, with the absence of any specific diagnostic investigation or criteria. We are presenting a seronegative juvenile Primary Sjogren’s syndrome (pSS) patient with all the challenges we had to confirm the diagnosis and a highlight on the role of MDT as the most sensitive tool.Description/MethodA 14-year-old female patient was first referred to our Paediatric and adolescent rheumatology department at the age of 10 with history of recurrent bilateral painful parotid swellings since the age of 3 with absence of ANA, RF, Anti-SSA-Ro and Anti-SSB-La antibodies repeatedly. From 2016 till 2019 she was under the care of ENT with recurrent complicated bilateral ear infections. Episodes tend to occur every 2-3 weeks and last between a few days to 2 weeks. Her events were associated with fever, fatigue, shivering, joint and leg pain, cervical lymphadenopathy, infrequent folliculitis, and headaches. No history to indicate mouth or eye dryness or significant repeated ulcers. Both of our patient’s mother and maternal grandmother have Behçet’s disease. Further blood investigation only showed mild hypergammaglobulinemia with mildly elevated ESR and CRP, normal LFT, U&Es, complements, muscle enzymes and thyroid function. HIV serology was negative and serum IgG4 subclass was normal. Many USSs confirmed parotitis. Parotid gland biopsy was not specific and indicated chronic parotitis with diffuse infiltration of mature lymphocytes, periductal lymphocytic inflammation and exocytosis of lymphocytes into the ductal epithelium. Focus score nearly reaching 50 cells. Plasma cell staining ruled out IgG4 related disease. Ophthalmic assessment ruled out eye involvement by the appearance of her eyes. The Oral Medicine Team confirmed the appearance of dry mucosa with minimal salivary flow from the parotid ducts, though it has not been subjectively reported to cause any problem before. Failed trial of colchicine, never been off-prednisolone for at least the last 2 years, tried Methotrexate which resulted in significant but not full improvement. Now she is on azathioprine and Hydroxychloquine, but still reporting flares. Escalation in treatment is required though there are some concerns about previous medication compliance, the actual severity of symptoms reported and the lack of current suitable accommodation.Discussion/ResultsDiagnosing pSS is quite challenging especially in seronegative patients due to the possibility of other non-autoimmune diseases causing recurrent parotid gland swellings, especially Recurrent Juvenile Idiopathic Parotitis with very young age of onset. With the persistence of symptoms and lack of an underlying infection, our patient ended up having a parotid biopsy. This was generally not specific, with a focus score close to the 50 mononuclear cells required as evidence of exocrine inflammation. This further added to the challenge of confirming an underlying autoimmune disease. Nine years into the disease course, our patient was confirmed to have objective evidence of dry mucosa and decreased salivary flow from the parotid ducts. This shows how important it is to assess salivary and lacrimal gland dysfunction in a child with suspected pSS, despite the absence of typical xerophthalmia and xerostomia. Considering the non-typical features (sero-negativity and the non-specific histopathology findings), our patient clinical picture was discussed in an MDT meeting including ENT, Histopathology and Rheumatology and the diagnoses of pSS was confirmed. The chronicity of the disease, significant improvement of the flare frequency and severity while on immunosuppressants, the reoccurence of significant flares when the patient was off-treatment (personal decision), and the objective evidence of poor salivary flow all supported the diagnosis of pSS later in the disease course. This case shows us how the typical adult features of pSS should not be strictly applied to the juvenile form of the disease. It also highlights the importance of having an MDT as the most sensitive available tool to confirm the diagnosis.Regarding lack of subjective full response, how do you think we can prove this objectively and what would be the most appropriate next step in treatment escalation?Key learning points/ConclusionA high index of suspicion is crucial to reach the diagnosis and to avoid irreversible damage in children with SS.Quadrable sero-negativity should not be looked at as an absolute exclusion criterion of juvenile pSS.Exclusion of other more common and diverse causes of parotitis is crucial.The typical adult features of SS should not be strictly applied to the juvenile form of the disease.MDT approach is the most sensitive tool to diagnose SS.When there is no subjectively reported ophthalmic or oral dryness, we would advocate sending suspected children of pSS for formal assessment of it- we understand the age-related challenges.Considering its rarity, we need to improve the general awareness of the juvenile form of the disease among the population and the medical practitioners.

P12 A case of MDA5-positive Juvenile Dermatomyositis complicated by Macrophage Activation Syndrome

Introduction/BackgroundHere we describe a case of juvenile dermatomyositis (JDM) complicated by macrophage activation syndrome (MAS), and the approach taken to treatment. Treatment with pulsed IV methylprednisolone was inadequate to control hyperinflammation in this case, so other treatment strategies were introduced. Macrophage activation syndrome appears to be less common in JDM than in systemic JIA or SLE, but it may be more frequent in MDA5-positive JDM.Description/MethodAn 11-year-old boy presented to paediatrics with a 6-week history of rash, mouth ulcers, anorexia and myalgia. He was previously well, with mild eczema only.On examination, he had rash affecting his face, periocular area, elbows and hands, with Gottron’s papules, plus arthritis of ankle and PIP joints. He had mild proximal muscle weakness with CMAS 45/52. JDM was diagnosed based on typical rash, proximal muscle weakness, raised muscle enzymes, muscle MRI and positive anti-MDA5.Echocardiography showed normal cardiac function whilst PFTs showed no evidence of interstitial lung disease.Blood results are shown in table 1. Findings included raised muscle enzymes, transaminitis, leucopenia, mild thrombocytopaenia and hyperferritinaemia. Two weeks previously, his FBC was normal.Table 1:P12 Laboratory results suggestive of MASDay 0 Day 1Day 4 Day 6 Day 10 Day 14Day 22 CK 1014 900 169 240 228 Ferritin 1880 2671 1769 5090 1784 3000 989 AST 490 574 321 696 208 273 66 Lymphocytes 1.1 0.9 1.3 0.5 1.0 0.8 1.5 IV methylprednisolone was started on day 2 of admission, however he remained persistently pyrexial, developing a rising ferritin and worsening transaminitis. This pattern was recognised as MAS.IV immunoglobulin was started on day 7, in addition to methotrexate and hydroxychloroquine. This resulted in resolution of fever and improved bloods. He was discharged on day 10 to continue outpatient management.After discharge, however, the ferritin climbed again. He was given further methylprednisolone and switched from methotrexate to ciclosporin on day 14. Following this, the features of MAS resolved, with ferritin falling. CMAS normalised within 2 months and his rash gradually improved.Once ferritin and FBC had normalised, ciclosporin was switched back to methotrexate. He continues on a treatment regimen of hydroxychloroquine, IVIg, methotrexate and reducing oral prednisolone with a plan to reassess after 6 months.Discussion/ResultsMAS, or secondary haemophagocytic lymphohistiocytosis (HLH), is a well-recognised phenomenon in systemic-JIA but may occur in other rheumatological conditions.The incidence of MAS in JDM is unknown. A systematic review found 12 case reports of MAS in JDM but was unable to estimate incidence or mortality. As with our patient, this case series suggested that JDM-related MAS may be difficult to treat, with methylprednisolone being inadequate in most. Likewise, it found that MAS tended to occur at presentation of JDM. A case series of adults with dermatomyositis complicated by MAS had similar findings.Cases of MDA5-positive dermatomyositis complicated by MAS have been reported in children and adults, suggesting an association. MDA5 positivity has also been associated with increased risk of interstitial lung disease, potentially suggesting a more severe phenotype.Key learning points/ConclusionMAS can occur occasionally in JDM and is most likely to present at diagnosis. In particular it should be considered in a patient presenting with features of JDM and associated cytopaenias or persistent fevers.Anti-MDA5 positive JDM may be associated with a higher incidence of MAS.IV methylprednisolone alone may be inadequate to treat MAS in JDM. A combination of IV methylprednisolone, IV immunoglobulin and oral ciclosporin successfully controlled clinical and biochemical features of MAS in this patient with JDM.

P11 An unusual case of Systemic Sclerosis/JDM overlap in a child with PAX8-related congenital hypothyroidism

Introduction/BackgroundJuvenile dermatomyositis is a rare inflammatory disease with a reported incidence of 0.8–4.1 per million children per year. It presents with a constellation of symptoms and signs of inflammation of skin and muscle, and is associated with significant morbidity if untreated. Juvenile systemic sclerosis (JSSc) is an even rarer rheumatological condition of childhood with significant risk of internal organ involvement, especially cardiopulmonary disease. We herewith present the case of a 7-year-old boy with history of hypothyroidism associated with a PAX8 gene variant who presented with clinical features of an overlap of Systemic Sclerosis with JDM with supportive autoantibody profile.Description/MethodA 7-year-old boy presented with a history of restricted range of movements in his hands – noted due to difficulties with pen grip – and calcinosis. He reported symptoms of fatigue, intolerance to cold with colour changes to hands and feet, stiffness of movements particularly in the morning, and infrequent episodes of choking. His past medical history was significant for hypothyroidism secondary to a paternally inherited PAX8 missense mutation, and there is a family history of Raynaud’s and hypothyroidism. A detailed examination identified diffusely swollen hands with sclerodactyly, calcinosis of his elbows and fingertips, and limited flexion of his fingers and wrists. He also had telangiectasia of his upper eyelids, Gottron’s papules over his knees and elbows, and sluggish circulation in his hands and feet. He had evidence of mild proximal muscle weakness.His investigations revealed mild elevation of muscle enzymes with normal inflammatory markers. His autoantibody profile showed a moderately positive ANA titre of 1600 with a nucleolar pattern, and was positive for anti-NXP2 and anti-SCL-100 antibodies MRI scan of the pelvis showed no evidence of myositis, echocardiogram was normal and a high-resolution CT scan of chest was normal with no features of interstitial lung disease.The overall picture was one of Systemic Sclerosis/JDM overlap with CREST syndrome. He was commenced on induction therapy with IV Methylprednisolone and Cyclophosphamide in view of the calcinosis. After three cycles of Cyclophosphamide and weaning course of oral corticosteroids, his energy levels are significantly improved and he has better overall mobility with no significant proximal muscle weakness (Childhood Myositis Assessment Scale score 49/53). However, flexion of his fingers remains limited albeit better; he has ongoing fingertip calcinosis but fewer lesions over his elbows. He has been commenced on weekly subcutaneous Methotrexate as he completes Cyclophosphamide.Discussion/ResultsThis patient had an unusual medical history of early onset thyroid dysfunction, the genetic testing for which revealed a missense PAX8 gene variant [c.49G>Ap.(Gly17Arg)] (also present in his father, who is euthyroid). This was classified as being of uncertain significance, although felt to clinically be the most likely cause for his hypothyroidism. There was no evidence to suggest that PAX8 gene mutations increased the risk of autoimmune conditions. There is evidence that PAX8 gene mutations, when expressed on malignant cells, may confer resistance to chemotherapy, which made us rethink the plan to commence him on Cyclophosphamide. However, we were reassured that in constitutional variants, there is no increased risk of cancer, and no known history of resistance to Cyclophosphamide.This patient also demonstrated an interesting antibody pattern, as he was positive for anti-NXP2 antibodies (indicating high risk for calcinosis) and anti-SCL-100 antibodies, which are associated with a clinical subset of patients with overlap of Systemic Sclerosis and JDM and associated with extensive extra-muscular features. He had two distinct clinical phenotypes of calcinosis, which is probably explained by the presence of two autoantibodies that increase the risk of calcinosis.Key learning points/ConclusionAlthough JDM has bimodal age group for presentation in childhood, only 3% of systemic sclerosis are seen in childhood, which makes this an extremely unusual presentation, given the age, gender and the overlap features (clinical and immunological).We explored whether this rare presentation could be linked to the underlying PAX8 gene mutations, but we could not find any association.With the clinical diagnosis of systemic sclerosis, it was important to rule out cardiopulmonary complications.The other consideration was regarding the choice of therapeutic agent - whether the germline PAX8 gene variants could increase the risk of malignancies or cause resistance to chemotherapeutic agents like Cyclophosphamide, for neither of which we could find any evidence.Extensive calcinosis cutis in this patient could be explained by the presence of two risk factors (CREST syndrome and JDM with NXP2 antibodies).

P60 A case of autoimmune inflammatory myositis in a patient with SLC29A3 spectrum disorder

Introduction/BackgroundThe SLC29A3 gene encodes the equilibrative nucleoside transporter hENT3. SLC29A3 spectrum disorder, an autosomal recessive disorder caused by mutations in this gene, is a rare multisystem disorder resulting in cutaneous manifestations (hyperpigmented, hypertrichotic and indurated patches of skin) and a variety of systemic features, with variable phenotypic expression. Along this spectrum are H syndrome and pigmented hypertrichotic dermatosis with insulin-dependent diabetes (PHID) syndrome. The majority of cases reported in the literature have been in patients of Arab descent. We report a case of a patient with SLC29A3 mutation who later developed features of autoimmune disease and myositis.Description/MethodAn 11-year-old girl with an established diagnosis of SLC29A3 mutation, dysosteosclerosis, camptodactyly and type 1 diabetes mellitus presented with a three-week history of intermittent fever, myalgia, muscle weakness and cervical lymphadenopathy. She had a non-specific rash over her eyelids, interphalangeal joints of both hands, torso and limbs. Her movements were restricted due to myalgia. She had no evidence of arthritis. Her creatine kinase was elevated (>1400 units/litre) and MRI of her thighs revealed evidence of myositis not akin to Juvenile Dermatomyositis distribution. An extensive investigation screen showed no evidence of infections. The bone marrow was hypocellular but there was no evidence of malignancy or histiocytosis. An autoinflammatory disease was suspected and the patient was treated with three pulses of IV methylprednisolone, to which she initially responded well but soon relapsed. Anakinra was trialled but this failed as the patient’s daily fevers persisted and her muscle weakness continued to worsen. Methotrexate was commenced and did not result in the desired reduction in prednisolone dose, so the patient was started on 4-weekly infliximab infusions. Following commencement of infliximab, the patient’s fever and rash resolved; her energy levels and muscle power improved and her muscle enzymes began to normalise. Repeat MRI showed her myositis was in remission. Infliximab was stopped after 13 doses due to side effects at the end of the infusions (tachycardia, hypertension and pyrexia). In addition, it was found that she had developed antibodies against infliximab and measured serum drug levels were low. Methotrexate was eventually stopped. The patient is now off all rheumatological treatment (as of February 2019) and she has not had reactivation of any of her symptoms.Discussion/ResultsThe patient we report had insulin-dependent diabetes mellitus, dysosteosclerosis and camptodactyly, three systemic features associated with SLC29A3 mutation. She presented concomitantly with signs of autoinflammatory disease and myositis. While up to 25% of patients with SLC29A3 mutation develop autoinflammatory features, to our knowledge, this is the first reported case of myositis in a patient with this mutation. Both the inflammatory features and myositis resolved following treatment with infliximab infusions. A number of case reports have described successful treatment of inflammation in SLC29A3 mutation with IL-6 inhibitors such as tocilizumab. The complete remission demonstrated in this case following infliximab infusions points to TNF-α inhibition as another potential therapeutic target. It is also interesting to note that our patient is now off all rheumatological treatment, which contrasts with other case reports in the literature where the patients have typically required maintenance immunomodulation therapy to remain asymptomatic. This case may therefore represent a new clinical subtype of SLC29A3 mutation with an autoimmune inflammatory myositis, rather than autoinflammatory as initially suspected, that carries a better prognosis. Further case reports of myositis in SLC29A3 mutation would help to build a clearer picture of its clinical presentation, prognosis and response to biologic therapies.Key learning points/Conclusion1. SLC29A3 spectrum disorder is a rare multisystem disorder that has only recently been recognised. By presenting this case report we hope to increase awareness of this condition and network with other clinicians who have encountered inflammatory disease associated with SLC29A3 mutation, either in their clinical practice or research.2. Up to a quarter of patients with SLC29A3 mutation present with autoinflammatory disease.3. We report on the first case of autoimmune inflammatory myositis in a patient with SLC29A3 mutation, to our knowledge.4. Our patient demonstrated complete remission of her inflammatory disease following treatment with infliximab, which may represent a new clinical subtype of SLC29A3 mutation with an autoimmune, rather than autoinflammatory, myositis that carries a better prognosis.