tacrolimus and Myositis

The management of patients with idiopathic inflammatory myopathy (IIM) remains a challenge given the systemic features beyond active myositis. That is, recognizing the inflammatory arthropathy, varying dermatomyositis rashes, and overt and occult features of interstitial lung disease in addition to myositis adds to the complexity of diagnosis and treatment of IIM. However, clinicians now have available many more immunosuppressive drugs as well as biologic agents for use in patients with myositis and other autoimmune diseases. Here, the use of these agents is reviewed and support based on available published literature is provided even though many studies have been small and results somewhat anecdotal. Glucocorticoids remain the initial treatment of choice in most instances and methotrexate and azathioprine are often used early in the treatment course. These agents are followed by other immunosuppressive drugs, for example mycophenolate mofetil, tacrolimus, cyclosporine and cyclophosphamide, some of which are used alone while combinations of these agents also provide an effective option. There is more rationale for the use of biologic agents such as rituximab from a mechanistic perspective and, given the incorporation of validated core set measures in assessing myositis patients, we can look forward to better designed clinical trials in the future.

Topics: Adrenocorticotropic Hormone; Adult; Azathioprine; Cyclophosphamide; Cyclosporine; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Immunologic Factors; Immunosuppressive Agents; Methotrexate; Mycophenolic Acid; Myositis; Tacrolimus

A 52-year-old woman was admitted to our hospital with muscle pain and an elevated creatine kinase level. She had experienced wrist pain at onset seven years ago. The initial possible diagnoses were rheumatoid arthritis and adult-onset Still disease. The patient received corticosteroid and immunosuppressant therapy but experienced deterioration of symptoms. The symptoms of muscle pain and mild creatine kinase elevation emerged four years prior to her visit. Further elevation of creatine kinase was observed for three months before her visit despite adjusting the immunosuppressant dose. On admission, she presented with muscle moderate weakness of the trunk and extremities and pain of the shoulder and medial thigh muscles. Elevation of muscle enzymes and inflammatory response were also detected, and the anti-PL7 antibody was positive. Muscle biopsy from biceps brachii revealed necrotizing myopathy with necrotic and regenerated muscle fibers. The final diagnosis was anti-PL7 antibody positive myositis. The patient was treated with a higher dose of prednisolone and an adequate dose of tacrolimus. Following this treatment, the symptoms were improved. Anti-ARS (aminoacyl t-RNA synthetase) antibodies such as anti-PL7 antibody are useful in diagnosis and for prognostic prediction. Further investigation of patients with anti-ARS antibodies positive myositis is required.

Topics: Amino Acyl-tRNA Synthetases; Autoantibodies; Female; Humans; Middle Aged; Myositis; Syndrome; Tacrolimus

To highlight recent advances in understanding the clinical spectrum, pathogenesis, and treatment of interstitial lung disease associated with inflammatory myositis and the antisynthetase syndrome.. In recent years, serologic tests to identify the less common antisynthetase antibodies and the anti-MDA-5 antibody have become commercially available. As a result, several large, retrospective analyses have illustrated both the pulmonary and non-pulmonary features associated with the antisynthetase syndrome and myositis-related interstitial lung disease. Notably, there is now a better appreciation for the heterogeneity of these syndromes and the prognostic value in accurately identifying the associated autoantibodies. Human cytokine profiling and murine models of muscle inflammation suggest that tRNA synthetases themselves may act to trigger an initial innate immune response, thus offering new insights into the pathophysiology of these diseases. Finally, although randomized clinical trials in patients with myositis-associated interstitial lung disease have not occurred, new observational studies suggest that cyclosporine, tacrolimus, and rituximab may be effective treatment options.. Recent research has provided a better understanding of the phenotype and prognosis that define interstitial lung disease in the setting of myositis and the antisynthetase syndrome. Although several therapeutic agents demonstrate promise, randomized trials are needed in order to establish the best clinical approach in these patients. Furthermore, additional research into the pathophysiology of this disease will be necessary to develop newer, more targeted therapeutics.

Topics: Antibodies, Monoclonal, Murine-Derived; Cyclosporine; Humans; Immunologic Factors; Lung Diseases, Interstitial; Myositis; Prognosis; Rituximab; Tacrolimus; Treatment Outcome

Currently, no standard treatment strategy has been established for immune-mediated necrotizing myopathy (IMNM). Here we present a case of IMNM which was successfully treated with intensive combined therapy with high-dose glucocorticoids, tacrolimus, and intravenous immunoglobulins. Her muscle weakness was rapidly progressive and severe so that she became bedridden one week after admission. She was complicated with dysphagia and had serum myogenic enzymes elevation, ventricular diastolic dysfunction, and interstitial lung disease. Serum anti-SRP antibody was positive and her muscle biopsy revealed many necrotic fibers with minimal inflammation. Further histological analysis demonstrated infiltration of phagocytic macrophages with deposition of membrane attack complex (C5b-9) in the necrotic muscle fibers, suggesting activation of complement pathway and macrophages as a pathomechanism of this disease. She was diagnosed as IMNM and was immediately initiated a combination therapy described above, which led to dramatic clinical improvements. Recent studies suggest that intravenous immunoglobulins and tacrolimus can inhibit the activation of complement pathway and macrophages. Our present case suggests that early initiation of intensive combined therapy including intravenous immunoglobulins and tacrolimus might be effective for preventing irreversible muscle damages by disrupting a pathogenic activation of complement and macrophages in IMNM.

Topics: Autoantibodies; Autoimmune Diseases; Complement Membrane Attack Complex; Female; Glucocorticoids; Humans; Immunoglobulins, Intravenous; Muscle Fibers, Skeletal; Muscular Diseases; Myositis; Tacrolimus

Primary effusion lymphoma (PEL) is a rare type of extranodal lymphoma, typically of a B-cell origin, which presents as lymphomatous effusion with no nodal enlargement or tumor masses. The development PEL is universally associated with human herpes virus-8 (HHV-8) infection. Cases of HHV-8-negative primary lymphomatous effusion have recently been reported and referred to as HHV-8-unrelated PEL-like lymphoma. Some cases of this disease have been reported in iatrogenic immunocompromised patients. The mechanisms responsible for the inhibitory effects of the discontinuation of immunosuppressants other than methotrexate (MTX) against the disease, which have been demonstrated for MTX-associated lymphoproliferative disorders, have not yet been elucidated. We describe a case of PEL-like lymphoma that developed in the course of antisynthetase syndrome and was treated with tacrolimus. A single dose of systemic chemotherapy did not improve lymphomatous effusion, whereas the discontinuation of tacrolimus resulted in the long-term remission of this disease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Epstein-Barr Virus Infections; Female; Herpesvirus 8, Human; Humans; Immunocompromised Host; Immunosuppressive Agents; Lymphoma, Primary Effusion; Middle Aged; Myositis; Prednisolone; Tacrolimus; Treatment Outcome; Vincristine; Withholding Treatment

Topics: Anti-Bacterial Agents; Antibodies, Antinuclear; Autoantigens; Cyclophosphamide; Extracorporeal Membrane Oxygenation; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Middle Aged; Myositis; Oxygen Inhalation Therapy; Respiratory Insufficiency; Ribonucleoproteins; Rituximab; SS-B Antigen; Tacrolimus

Patients with myositis-associated interstitial lung disease (MA-ILD) are often refractory to conventional treatment, and predicting their response to therapy is challenging. Recent case reports and small series suggest that tacrolimus may be useful in refractory cases.. A retrospective cohort study of patients with MA-ILD comparing clinical characteristics between those who responded to or failed conventional treatment. In those who failed conventional treatment and received adjunctive tacrolimus, response to tacrolimus was measured by the improvement in myositis, ILD, and change in the dose of glucocorticoids.. Thirty-one of 54 patients (57%) responded to conventional treatment based on the predefined variables of improvement in myositis and/or ILD. Patients with polymyositis (PM)-ILD were more likely to respond to conventional treatment than those with dermatomyositis (DM)-ILD (67% vs 35%, p = 0.013). Twenty-three patients failed conventional treatment, 18 of whom subsequently received adjunctive tacrolimus. Ninety-four percent had improvements in ILD and 72% showed improvement in both myositis and ILD. The mean doses of prednisone decreased from baseline by 65% at 3-6 months (p = 0.002) and 81% at 1 year (p < 0.001).. Patients with PM-ILD were more likely to respond to conventional treatment than patients with DM-ILD, but clinical characteristics and serology did not otherwise predict response to therapy. A majority of patients with MA-ILD refractory to conventional therapy improved while receiving tacrolimus and were able to decrease their dose of both glucocorticoids and other disease-modifying antirheumatic drugs.

Topics: Adult; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Prednisone; Retrospective Studies; Tacrolimus; Treatment Failure; United States

Thrombotic microangiopathy (TMA) is a rare complication associated with the use of calcineurin inhibitors in lung transplantation, irrespective of the underlying disease of the graft recipient. It usually occurs in incomplete forms, complicating and delaying diagnosis until damage is already irreversible. It is unrelated to time from transplantation and often presents with concomitant infection, which tends to confound diagnosis. The cases discussed here have a common causative agent and all present with concomitant infection. Treatment recommendations have changed in recent years with the introduction of plasmapheresis or, more recently, the availability of the antibody eculizumab. Notwithstanding, the most cost-effective measure is withdrawal or switching of the calcineurin inhibitor. TMA is an underdiagnosed clinical entity that should be considered in the management of transplantation patients.

Topics: Abscess; Candida glabrata; Candidiasis; Creatinine; Disease Susceptibility; Drug Substitution; Erythrocytes, Abnormal; Everolimus; Female; Hemoglobins; Humans; Immunosuppressive Agents; L-Lactate Dehydrogenase; Lung Transplantation; Male; Middle Aged; Myositis; Nocardia Infections; Platelet Transfusion; Pneumonia; Postoperative Complications; Tacrolimus; Thrombotic Microangiopathies; Young Adult

In the treatment of polymyositis (PM) and dermatomyositis (DM), muscle inflammation and underlying autoimmunity need to be suppressed promptly; however, catabolic effects of corticosteroids such as myopathy can be detrimental in PM/DM. In this study, we aimed to assess the corticosteroid-sparing effect of tacrolimus in the initial treatment of PM/DM.. We retrospectively identified 19 PM/DM patients who received initial treatment with prednisolone at an initial dose of 1 mg/kg/day (Conventional Monotherapy, our standard therapy before 2008) and 23 patients with tacrolimus plus prednisolone at an initial dose 0.8 mg/kg/day (Tacrolimus Combination, our standard therapy after 2008). Data until 36 months after commencing treatment were collected.. There were no statistically significant differences in baseline characteristics between two groups. Median daily dose of prednisolone in the Tacrolimus Combination Group was significantly lower than that in the Conventional Monotherapy Group during the study period, whereas the proportion of patients who required additional immunosuppressive medications for remission induction was comparable. Remission was achieved in all patients, except one who died of refractory interstitial lung disease after receiving Conventional Monotherapy. The time required for creatine kinase normalization and relapse rate was comparable between two groups. The period of hospitalization for initial treatment was significantly shorter and survival without serious infection or relapse tended to be longer in the Tacrolimus Combination than the Conventional Monotherapy.. This study provides real-life data which demonstrate that tacrolimus has a corticosteroid-sparing effect and reduces the length of hospitalization period for the initial treatment of PM/DM.

Topics: Adrenal Cortex Hormones; Adult; Dermatomyositis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Length of Stay; Male; Middle Aged; Myositis; Polymyositis; Prednisolone; Retrospective Studies; Tacrolimus

Macrophagic myofascitis (MMF) is an unusual inflammatory myopathy characterized by muscle infiltration by macrophages and lymphocytes. Here, we describe a case of MMF which is associated with rheumatoid arthritis. A 53-year-old Japanese rheumatoid arthritis (RA) patient presented with focal tenderness of lower extremities. Magnetic resonance imaging showed evidence of myofascitis involving fascias of anterior tibialis muscle. Muscle biopsy showed a unique pathological pattern of MMF. MMF is known to be associated with vaccination containing aluminum. However, our case was not related to aluminum containing vaccinations and etiologies are unknown. The possible link needs to be discussed.

Topics: Arthritis, Rheumatoid; Biopsy; Fascia; Female; Gait Disorders, Neurologic; Humans; Immunosuppressive Agents; Leg; Macrophages; Magnetic Resonance Imaging; Middle Aged; Muscle Weakness; Muscle, Skeletal; Myofascial Pain Syndromes; Myositis; Prednisolone; Tacrolimus; Treatment Outcome

Topics: Cyclosporine; Female; Humans; Middle Aged; Muscle Weakness; Myositis; Nail Diseases; Pyoderma Gangrenosum; Tacrolimus; Toes; Treatment Outcome

To assess the efficacy of tacrolimus in patients with anti-aminoacyl-transfer RNA synthetase (anti-aaRS)-associated interstitial lung disease (ILD) and idiopathic inflammatory myopathy (IIM).. Ninety-eight patients with anti-aaRS autoantibodies were identified in our IIM cohort of 536 patients. The medical records of 15 patients with anti-aaRS-associated ILD treated with tacrolimus between 1992 and 2003 were retrospectively reviewed. Pulmonary parameters of response included forced vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide. Manual muscle testing results, serum creatine kinase (CK) levels, and the daily corticosteroid dosage were used to assess improvement in myositis. Random coefficient modeling considering polynomials of time was used to assess the clinical response to tacrolimus.. All patients, except for 1, who had pure ILD, had definite or probable IIM. Two patients received tacrolimus for fewer than 3 months, and their data were not analyzed. For the remaining 13 patients, the mean age at onset of ILD was 46.9 years, and the mean duration of pulmonary disease was 14.7 months. Twelve patients had anti-histidyl-transfer RNA synthetase autoantibody (anti-Jo-1) and 1 had anti-alanyl-transfer RNA synthetase autoantibody (anti-PL-12). Patients received tacrolimus for an average of 51.2 months. A significant improvement was observed in all pulmonary parameters measured. The serum CK level declined significantly, and 10 patients had either an improvement in muscle strength or maintained normal muscle strength. A statistically significant reduction in the corticosteroid dosage was also observed.. Tacrolimus is a well-tolerated and effective therapy for managing refractory ILD and myositis in anti-aaRS-positive patients.

Topics: Adult; Aged; Alanine-tRNA Ligase; Amino Acyl-tRNA Synthetases; Autoantibodies; Cohort Studies; Female; Histidine-tRNA Ligase; Humans; Immunosuppressive Agents; Lung Diseases, Interstitial; Male; Middle Aged; Myositis; Retrospective Studies; Tacrolimus; Treatment Outcome

The patient is a 62-year-old man who was diagnosed with myasthenia gravis and invasive thymoma at the age of 45 years, and had received treatment by extended thymectomy and radiotherapy. At the age of 61, he had suffered from a myasthenic crisis, and been administered immunoadsorption therapy under managed ventilatory care. Treatment had then been continued with steroids; however, due to subsequent deterioration of his diabetic state, treatment was switched to the immunosuppressant drug tacrolimus. Three months after the commencement of tacrolimus administration, the patient developed generalized malaise and dyspnea. The serum creatine phosphokinase (CPK) level was abnormally elevated, and abnormal electrocardiographic findings were noted, including atrioventricular dissociation and ventricular escape contraction. Steroid pulse therapy was therefore initiated, however, 4 days later, the patient suddenly died. Autopsy examination revealed inflammatory cell infiltration with giant cells in the myocardium, diffuse myocardial degeneration, and polymyositis. The case was therefore considered as one with the syndrome of myasthenia gravis, polymyositis, giant cell myocarditis, and thymoma.

Topics: Alopecia; Creatine Kinase; Dyspnea; Electrocardiography; Giant Cells; Humans; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Myocarditis; Myocardium; Myositis; Polymyositis; Radiography, Thoracic; Tacrolimus; Thymoma; Thymus Neoplasms; Time Factors; Treatment Outcome

A 55-year-old Caucasian man who had received a second kidney graft in July 1993, was switched from cyclosporine to tacrolimus in June 2000 due to deterioration of renal function. Thereafter, he began to complain of muscle cramps in both quadriceps with an increased CPK and EMG findings of polyneuropathy. A muscle biopsy demonstrated acute myositis. Prednisone was administered with amelioration of the patient's symptoms, but with persistently increased CPK and myoglobin levels. In February 2001, mycophenolate mofetil was introduced and tacrolimus tapered to 3 mg daily to seek a toxic role of this immunosuppressant, since there was no other cause of myositis. A sudden decrease in CPK was observed, but the complete normalization took place only after its withdrawal in September 2002. This case represents a tacrolimus-associated myositis.

Topics: Electromyography; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Myoglobin; Myositis; Reoperation; Tacrolimus; Treatment Outcome

Experimental autoimmune myositis (EAM) is a good model of human inflammatory myopathy. We induced EAM in SJL/J mice by injection with myosin and treated inflammatory changes with FK506. The mice developed inflammatory changes after the fifth myosin injection. After treatment with FK506, inflammation was suppressed and central nuclei of the muscle fibers increased. These findings indicate that FK506 is effective in the treatment of EAM. The data suggests that FK506 inhibits interaction with calcineurin. Intercellular adhesion molecule-1 (ICAM-1) positive cells were present in the inflammatory and non-inflammatory areas of EAM. The FK506-treated group stained more weakly for ICAM-1 than the untreated EAM group.

Topics: Animals; Cell Nucleus; Female; Immunohistochemistry; Immunosuppressive Agents; Intercellular Adhesion Molecule-1; Mice; Mice, Inbred Strains; Muscle, Skeletal; Myosins; Myositis; Nervous System Autoimmune Disease, Experimental; Phagocytosis; Tacrolimus; Treatment Outcome