Immune-mediated necrotizing myopathy (NAM) related to SARS-Cov-2 infection: a case report.

BACKGROUND: There is a growing body of evidence that severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) or COVID-19 infection is associated with the development of autoimmune diseases. A recent systematic review reported that the new-onset autoimmune disorders during or after COVID-19 infection included inflammatory myopathies such as immune-mediated necrotizing myopathies. CASE PRESENTATION: We described a 60-year-old man diagnosed with COVID-19 infection and later presented with a two-week history of myalgia, progressive limb weakness, and dysphagia. He had a Creatinine Kinase (CK) level of more than 10,000 U/L, was strongly positive for anti-signal recognition particle (SRP) and anti-Ro52 antibody, and a muscle biopsy revealed a paucity-inflammation necrotizing myopathy with randomly distributed necrotic fibers, which was consistent with necrotizing autoimmune myositis (NAM). He responded well clinically and biochemically to intravenous immunoglobulin, steroids and immunosuppressant and he was able to resume to his baseline. CONCLUSION: SARS-CoV-2 may be associated with late-onset necrotizing myositis, mimicking autoimmune inflammatory myositis.

EULAR points to consider for the diagnosis and management of rheumatic immune-related adverse events due to cancer immunotherapy with checkpoint inhibitors.

BACKGROUND: Rheumatic and musculoskeletal immune-related adverse events (irAEs) are observed in about 10% of patients with cancer receiving checkpoint inhibitors (CPIs). Given the recent emergence of these events and the lack of guidance for rheumatologists addressing them, a European League Against Rheumatism task force was convened to harmonise expert opinion regarding their identification and management. METHODS: First, the group formulated research questions for a systematic literature review. Then, based on literature and using a consensus procedure, 4 overarching principles and 10 points to consider were developed. RESULTS: The overarching principles defined the role of rheumatologists in the management of irAEs, highlighting the shared decision-making process between patients, oncologists and rheumatologists. The points to consider inform rheumatologists on the wide spectrum of musculoskeletal irAEs, not fulfilling usual classification criteria of rheumatic diseases, and their differential diagnoses. Early referral and facilitated access to rheumatologist are recommended, to document the target organ inflammation. Regarding therapeutic, three treatment escalations were defined: (1) local/systemic glucocorticoids if symptoms are not controlled by symptomatic treatment, then tapered to the lowest efficient dose, (2) conventional synthetic disease-modifying antirheumatic drugs, in case of inadequate response to glucocorticoids or for steroid sparing and (3) biological disease-modifying antirheumatic drugs, for severe or refractory irAEs. A warning has been made on severe myositis, a life-threatening situation, requiring high dose of glucocorticoids and close monitoring. For patients with pre-existing rheumatic disease, baseline immunosuppressive regimen should be kept at the lowest efficient dose before starting immunotherapies. CONCLUSION: These statements provide guidance on diagnosis and management of rheumatic irAEs and aim to support future international collaborations.

Serum Protein Profiling Reveals a Landscape of Inflammation and Immune Signaling in Early-stage COVID-19 Infection.

Coronavirus disease 2019 (COVID-19) is a highly contagious infection and threating the human lives in the world. The elevation of cytokines in blood is crucial to induce cytokine storm and immunosuppression in the transition of severity in COVID-19 patients. However, the comprehensive changes of serum proteins in COVID-19 patients throughout the SARS-CoV-2 infection is unknown. In this work, we developed a high-density antibody microarray and performed an in-depth proteomics analysis of serum samples collected from early COVID-19 (n = 15) and influenza (n = 13) patients. We identified a large set of differentially expressed proteins (n = 132) that participate in a landscape of inflammation and immune signaling related to the SARS-CoV-2 infection. Furthermore, the significant correlations of neutrophil and lymphocyte with the CCL2 and CXCL10 mediated cytokine signaling pathways was identified. These information are valuable for the understanding of COVID-19 pathogenesis, identification of biomarkers and development of the optimal anti-inflammation therapy.

Autoimmune and rheumatic musculoskeletal diseases as a consequence of SARS-CoV-2 infection and its treatment.

The coronavirus disease-2019 (COVID-19) pandemic is likely to pose new challenges to the rheumatology community in the near and distant future. Some of the challenges, like the severity of COVID-19 among patients on immunosuppressive agents, are predictable and are being evaluated with great care and effort across the globe. A few others, such as atypical manifestations of COVID-19 mimicking rheumatic musculoskeletal diseases (RMDs) are being reported. Like in many other viral infections, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection can potentially lead to an array of rheumatological and autoimmune manifestations by molecular mimicry (cross-reacting epitope between the virus and the host), bystander killing (virus-specific CD8 + T cells migrating to the target tissues and exerting cytotoxicity), epitope spreading, viral persistence (polyclonal activation due to the constant presence of viral antigens driving immune-mediated injury) and formation of neutrophil extracellular traps. In addition, the myriad of antiviral drugs presently being tried in the treatment of COVID-19 can result in several rheumatic musculoskeletal adverse effects. In this review, we have addressed the possible spectrum and mechanisms of various autoimmune and rheumatic musculoskeletal manifestations that can be precipitated by COVID-19 infection, its therapy, and the preventive strategies to contain the infection.

Serological evidence of Zika virus infection in febrile patients at Greater Accra Regional Hospital, Accra Ghana.

OBJECTIVE: Increase in the evidence of global occurrence of Zika viral infection suggests that in Africa the circulation of the virus which causes 80% of asymptomatic infection could be undetected and/or overlooked. We sought to serologically detect Zika virus infection in febrile patients at Greater Accra Regional Hospital, Ghana. RESULTS: Of the 160 patient serum samples analyzed, 33 were found to have antibodies against Zika virus infection. Among the sero-positives 30 (91%) of the cases were anti-Zika virus IgM with the 21-30-year age group recording the highest number of 8 (26%) and 2 (7%) cases being the least for the 61 years and above age group. All sero-positive febrile patients developed at least one symptom consistent with Zika virus infection: 33 (100%) fever, 25 (76%) muscle pain, 24 (73%) joint pain, and conjunctivitis 2 (6%). Digestive symptoms recorded include 16 (49%) nausea, 12 (36%) vomiting and diarrhea 18 (55%). In addition, 28 (85%) loss of appetite, 14 (75%) rapid respiration and chest pain 15 (42%) were reported by seropositive febrile patients. Our data indicates exposure to Zika virus which suggests the possible circulation of the virus among febrile patients in Ghana with a sero-prevalence rate of 20.6%.

Multiple Cold-Water Immersions Attenuate Muscle Damage but not Alter Systemic Inflammation and Muscle Function Recovery: A Parallel Randomized Controlled Trial.

The aim of this study was to investigate the effects of multiple cold-water immersions (CWIs) on muscle function, markers of muscle damage, systemic inflammation and ECM degradation following exercise-induced muscle damage (EIMD). Thirty physically active males were randomly assigned to either a control (n = 15) or cold-water immersion (CWI) group (n = 15). The CWI group performed one immersion (10 °C for 20 min) at post-exercise and every 24 h for the following 72 h, while the control group remained in a seated position during these corresponding periods. Muscle strength, vertical jump height, muscle thickness, delayed-onset muscle soreness (DOMS), systemic creatine kinase (CK), C-reactive protein (CRP), inflammatory cytokines and matrix metalloproteinase-2 (MMP-2) activity were assessed at Pre, Post, 24, 48, 72, 96 and 168 h following EIMD. No significant time × group interaction was obtained for muscle strength, vertical jump height recovery and MMP-2 activity (p > 0.05). At 24 h, muscle thickness from the CWI group returned to baseline and was lower than the control (p = 0.04). DOMS returned to baseline at 168 h for the CWI group (p = 0.109) but not for the control (p = 0.008). At 168 h, CK showed a time-group difference with a greater peak for the control group (p = 0.016). In conclusion, multiple CWIs attenuated muscle damage, but not altered systemic inflammation and muscle function recovery.

Statin-induced myalgia and myositis: an update on pathogenesis and clinical recommendations.

INTRODUCTION: Musculoskeletal manifestations are well-recognized side effects of treatment with statins. New advances in this field have appeared in recent years. This review focuses on the diagnosis of these conditions and their underlying pathogenesis, in particular immune-mediated necrotizing myopathy. Areas covered: Clinical phenotypes including rhabdomyolysis, myalgia and/or mild hyperCKemia, self-limited toxin statin myopathy, and immune-mediated necrotizing myopathy are herein described. Therapeutic recommendations and a diagnostic algorithm in statin-associated myopathy are also proposed. The etiology and pathogenesis of statin-induced myopathy has mainly focused on the anti-HMGCR antibodies and the responsibility of the immune-mediated necrotizing myopathy is discussed. The fact that patients who have not been exposed to statins may develop statin-associated autoimmune myopathy with anti-HMGCR antibodies is also addressed. The literature search strategy included terms identified by searches of PubMed between 1969 and December 2017. The search terms 'myositis', 'statin-induced autoimmune myopathy', 'immune-mediate necrotizing myopathy', 'statins', 'muscular manifestations', and 'anti-HMGCR antibodies' were used. Expert commentary: Full characterization of the known phenotypes of statin toxicity and the specific role of the anti-HMGCR in those exposed and not exposed (i.e. juvenile forms) to statins and in some types of neoplasms is of paramount relevance.

Effects of Products Containing Bacillus subtilis var. natto on Healthy Subjects with Neck and Shoulder Stiffness, a Double-Blind, Placebo-Controlled, Randomized Crossover Study.

Neck and shoulder stiffness is a typical subjective symptom in developed countries. This stiffness is caused by factors such as muscle tension and poor blood flow, leading to reduce work efficiency and diminish QOL. NKCP®, a natto-derived dietary food supplement whose main component is bacillopeptidase F, has antithrombotic, fibrinolytic, and blood viscosity-lowering effects. Here, we investigated the effect of NKCP® on neck and shoulder stiffness in a double-blind placebo-controlled randomized crossover study. Thirty subjects with neck and shoulder stiffness were randomly divided into 2 groups and ingested 250 mg of NKCP® or placebo daily for 4 weeks. Headache score significantly improved in the NKCP® group compared to the placebo group. Moreover, NKCP® significantly improved the score of visual analogue scale for neck and shoulder stiffness and pain, reduced muscle stiffness of the neck, and increased the skin surface temperature of neck and shoulders, compared to before ingestion. No adverse effects were observed during this study. These results suggest that NKCP® may alleviate headaches and chronic neck and shoulder stiffness and pain.

A low-dose, 6-week bovine colostrum supplementation maintains performance and attenuates inflammatory indices following a Loughborough Intermittent Shuttle Test in soccer players.

PURPOSE: The aim of the study was to investigate the effect of a 6-week, low-dose bovine colostrum (BC) supplementation on exercise-induced muscle damage (EIMD) and performance decline in soccer players following the Loughborough Intermittent Shuttle Test (LIST) during a competitive season period. METHODS: In a double-blind, randomized, placebo-controlled design, two groups of soccer players were allocated to a 3.2 g/day of whey protein (WP, N = 8) or BC (N = 10) and performed a pre- and a post-supplementation LIST. Maximum isometric voluntary contraction, squat jump (SQJ), countermovement jump, muscle soreness, blood cell counts, creatine kinase (CK), C-reactive protein (CRP) and interleukin-6 (IL-6) were monitored for 2, 24, 48, 72 h post-LIST. RESULTS: LIST induced transient increases in leukocytes, granulocytes, CK, muscle soreness, CRP, IL-6 and declines in lymphocytes and performance indices. Supplementation resulted in a faster recovery of SQJ, CK and CRP compared to pre-supplementation kinetics (trial × time: p = 0.001, 0.056, 0.014, respectively) and lower incremental area under the curve (iAUC) for IL-6, only in the BC group [pre-: 31.1 (6.78-46.9), post-: 14.0 (-0.16 to 23.5) pg h/ml, p = 0.034]. Direct comparison of the two groups after supplementation demonstrated higher iAUC of SQJ [WP: -195.2 (-229.0 to (-52.5)), BC: -15.8 (-93.2 to 16.8) cm h, p = 0.034], a trend for lower iAUC of CK in the BC group [WP: 18,785 (4651-41,357), BC: 8842 (4807-14,802) U h/L, p = 0.081] and a significant intervention × time interaction for CRP (p = 0.038) in favor of BC. CONCLUSIONS: Post-exercise EIMD may be reduced and performance better maintained by a low dose of BC administration following LIST in soccer players.

Cutaneous and Systemic Findings Associated With Nuclear Matrix Protein 2 Antibodies in Adult Dermatomyositis Patients.

OBJECTIVE: To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with antinuclear matrix protein 2 (anti-NXP-2) antibodies. METHODS: We conducted a retrospective cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. An electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti-NXP-2 antibodies were assayed by immunoprecipitation using NXP-2 produced by in vitro transcription/translation. RESULTS: Antibodies to NXP-2 were detected in 20 of the 178 patients (11%). Anti-NXP-2 antibodies were associated with male sex (50% versus 25%; P = 0.02), dysphagia (74% versus 39%; P = 0.006), myalgia (89% versus 52%; P = 0.002), peripheral edema (35% versus 11%; P = 0.016), and calcinosis (37% versus 11%; P = 0.007). These patients were less likely to be clinically amyopathic (5% versus 23%; P = 0.08). Five of the 20 patients with anti-NXP-2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti-NXP-2 antibodies, except a decreased frequency of Gottron's sign (44% versus 75%; P = 0.012) and a greater likelihood of having mild skin disease. CONCLUSION: Dermatomyositis patients with anti-NXP-2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema, and significant dysphagia, despite having milder inflammatory skin disease.

Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature.

OBJECTIVE: Immune checkpoint inhibitors (ICIs) are improving prognoses in advanced stage cancers, but they also lead to immune-related adverse events (IRAEs). IRAEs targeting many organ systems have been reported, but musculoskeletal and rheumatic IRAEs have not been well-characterized. We systematically reviewed published literature on musculoskeletal and rheumatic IRAEs to better understand prevalence and clinical characteristics. METHODS: Medline and CENTRAL databases were searched for articles reporting rheumatic and musculoskeletal IRAEs secondary to ICI treatment. After screening abstracts and full texts in duplicate, clinical features, prevalence, and treatment data were extracted and summarized. RESULTS: A total of 1,725 unique abstracts were screened; 231 contained original data and were about ICIs and went to full-text screening. Fifty-two of these contained information about musculoskeletal or rheumatic IRAEs or about treatment with ICIs in preexisting autoimmune disease. Of these, 33 were clinical trials, 3 were observational studies, and 16 were case reports or series. Arthralgia prevalence in clinical trials ranged 1-43%, and myalgia was reported in 2-20%. Arthritis was reported in 5 of 33 clinical trials, and vasculitis was reported in only 2. One observational study and 3 case reports described patients with preexisting autoimmune disease treated with ICIs. Case reports included development of inflammatory arthritis, vasculitis, myositis, and lupus nephritis. CONCLUSION: Arthralgia and myalgia have been reported commonly in patients treated with ICIs. The prevalence of rheumatic IRAEs such as inflammatory arthritis, vasculitis, and sicca syndrome is less clear from current evidence. There is limited observational and case-level evidence describing ICI use in patients with preexisting autoimmune disease.

Muscle damage, inflammatory, immune and performance responses to three football games in 1 week in competitive male players.

PURPOSE: We examined effects of a three-game, 1-week microcycle (G1, G2, G3) on recovery of performance and inflammatory responses in professional male footballers. METHODS: Players were randomized into an experimental (EXP; N = 20) and a control group (CON; N = 20). Blood was drawn and repeated sprint ability (RSA), muscle soreness and knee range of motion (KJRM) were determined pre- and post-games and during recovery. RESULTS: High-intensity running during G2 was 7-14% less compared to G1 and G3. RSA declined in EXP by 2-9% 3 days post-game with G2 causing the greatest performance impairment. In EXP, game play increased muscle soreness (~sevenfold) compared to CON with G2 inducing the greatest rise, while KJRM was attenuated post-game in EXP compared to CON (5-7%) and recovered slower post G2 and G3 than G1. CK, CRP, sVCAM-1, sP-Selectin and cortisol peaked 48 h post-games with G2 eliciting the greatest increase. Leukocyte count, testosterone, IL-1ß and IL6 responses, although altered 24 h post each game, were comparable among games. Plasma TBARS and protein carbonyls rose by ~50% post-games with G2 eliciting the greatest increase 48 h of recovery. Reduced to oxidized glutathione ratio declined for 24 h post all games with G2 displaying the slowest recovery. Total antioxidant capacity and glutathione peroxidase activity increased (9-56%) for 48 h in response to game play. CONCLUSION: In summary, post-game performance recovery and inflammatory adaptations in response to a three-game weekly microcycle displayed a different response pattern, with strong indications of a largest physiological stress and fatigue after the middle game that was preceded by only a 3-day recovery.

[Myopathy in patients with Waldenströms macroglobulinemia. A case study and an overview of autoimmune expressions of type IgM monoclonal immunoglobulins]. / Myopatie pri Waldenströmove makroglobulinemii. Popis prípadu a prehled autoimunitních projevu monoklonálních imunoglobulinu typu IgM.

Waldenströms macroglobulinemia which was manifested by muscle pain and anemia. The female patient had suffered from back pain for about 3 years before she came to our clinic. In the last year pain in the muscles of the upper and lower extremities developed in addition to back pain. This led to the suspicion of polymyositis. However this was not confirmed by a special examination. The patient was diagnosed with clearly established infiltration of lympho-plasmacytic lymphoma and 10.8 g/l of type IgM monoclonal immunoglobulin in the bone marrow. Serum myoglobin levels and serum CK activity were repeatedly significantly increased. Therefore the treatment with anti-CD20 monoclonal antibody (Mabthera) 375 mg/m2 i. v. was started, administered once a month, with cyclophosphamide 500 mg/m2 i. v. on days 1 and 15 of a 28-day cycle, and dexamethasone 20 mg from 1st through to 4th days and 15th through to 18th days of the treatment cycle. There were 8 cycles planned. Already after a 5th cycle, the disappearance of monoclonal immunoglobulin (negative immunofixation), normalisation of myoglobin and CK values and significant relief from muscle pain were achieved. The hemoglobin concentrations before treatment were significantly reduced, while they were normalised after treatment. After 5 cycles, the complete remission of Waldenströms disease was reached according to biochemical parameters, and normalisation of the serum myoglobin and creatine kinase levels was achieved.

Risk factors for subclinical inflammation in children with Familial Mediterranean fever.

Familial Mediterranean fever (FMF) is the most common autosomal recessive inherited inflammatory disease characterized by attacks of painful inflammation. Some patients with FMF have subclinical inflammation persisting between the attacks. We aimed to identify the demographic, clinical and genetic risk factors for subclinical inflammation in children with FMF. The medical records of the children with FMF were evaluated retrospectively for acute-phase response along with gender, age at the onset of symptoms and at the time of diagnosis, clinical signs and symptoms, the presence of amyloidosis and MEFV genotype. Patients with persistently elevated acute-phase response between the attacks were considered to have subclinical inflammation. Patients with or without subclinical inflammation (Group 1 and Group 2, respectively) were compared for the parameters defined above. Independent risk factors for subclinical inflammation were identified by multivariate logistic regression analysis. There were 105 children (male/female: 52/53) who were compliant on colchicine treatment. Subclinical inflammation was detected in 22 (20 %) patients. Group 1 had significantly higher rate of myalgia, arthritis/arthralgia, erysipelas like erythema, amyloidosis, protracted febrile myalgia and M694V mutation compared with Group 2. However, only the presence of myalgia and erysipelas like erythema were found to be independent risk factors for subclinical inflammation (OR 9.8 and 5.9, respectively). Children with FMF who have myalgia and erysipelas like erythema during the attacks are particularly at risk of ongoing inflammation and should be closely monitored for subclinical inflammation even during attack-free periods.

Immunological effects of massage after exercise: A systematic review.

OBJECTIVE: The objective of this review was to determine whether immune parameters can be modulated by massage after intense physical activity. METHODS: A search was conducted in Pub Med Medline, PEDro, and Cochrane databases, using the key words: "massage", "myofascial release", "acupressure", "recovery", and "warm up" combined with "exercise", "exercise-induced muscle damage", "sport", "immunology", and lymphocytes" independently. Only controlled studies published between 1970 and 2012 were selected, with no restrictions regarding publication language. The CONSORT Declaration was applied to assess the quality of the selected studies. RESULTS: The initial search identified 739 publications in the databases, of which only 5 met the review inclusion criteria. A positive relationship between immunological recovery and post-exercise massage was reported by some of these studies but not by others. CONCLUSION: There is preliminary evidence that massage may modulate immune parameters when applied after exercise, but more research is needed to confirm this possibility.

A CASE OF POLYMYOSITIS WITH INTERSTITIAL LUNG DISEASE ONSET.

Polymyositis is an idiopathic inflammatory myopathy of unknown aetiology that affect skeletal muscles causing symmetrical, proximal muscle weakness, and also other internal organs. The investigations reveal elevated skeletal muscle enzyme levels and characteristic electromyography (EMG) and muscle biopsy findings. Pulmonary involvement in polymyositis includes respiratory muscle weakness, aspiration pneumonia, interstitial lung disease, infection and drug-induced pneumonia. We expose the case of a young woman (47 years old) who presented to the Pulmonology Clinic with fever, cough, purulent sputum, discrete myalgia, being diagnosed at that moment with interstitial lung disease and treated with antibiotics, low dose of corticosteroids and symptomatic drugs. The evolution was slowly favorable for the respiratory impairment, but the patient developed exacerbated myalgia, muscle weakness, reaching even the impossibility of maintaining orthostatism, and also joint pain. Biological investigations revealed an important hepatocytolysis syndrome and also increased levels of muscle enzyme. The hypothetical diagnosis was polymyositis and to sustain this theory it was performed a muscle biopsy. The patient was transferred afterwards to the Rheumatology Clinic, in order to perform other specific investigations. In our clinic the patient maintained elevated levels of skeletal muscle enzymes and the muscle biopsy revealed polymyositis findings. Also immunological investigations objectified the presence of Jo1 antibodies. Therefore we pleaded for the diagnosis of idiopathic polymyositis, acute form. A multidisciplinary approach is needed in order to establish an accurate diagnosis and to institute a proper treatment.