tacrolimus and Thymoma

Myasthenia gravis (MG) is an autoimmune disease mediated by autoantibodies to the striated muscle tissue. It is often treated by thymectomy. We review recent studies to investigate the biological implications of thymectomy. In anti-acetylcholine receptor antibody (anti-AchR Ab)-positive patients without a thymoma, abnormal germinal center formation in the thymus seems to play an essential role in the pathogenesis of MG. Specific differentiation of B cells producing anti-AchR Ab takes place uniquely in the thymus, and thymectomy is thought to assist in terminating the provision of high-affinity anti-AchR antibody-producing cells to peripheral organs. Thymectomy is not indicated for anti-AchR Ab-negative MG patients who are antimuscle specific kinase antibody (anti-MuSK Ab)-positive, although some anti-MuSK Ab-negative patients may benefit from the procedure. A thymoma can be considered as an acquired thymus with insufficient function of negative selection. The resection of a thymoma is thought to terminate the production of self-reactive T cells. Thus, the biological implications of thymectomy for MG have been partially revealed. Nevertheless, additional studies are needed to elucidate the ontogeny of T cells that recognize AchR and the mechanism of the activation of anti-AchR antibodies producing B cells.

Topics: Adult; Age Factors; Autoantibodies; B-Lymphocytes; Cyclosporine; Humans; Immunosuppressive Agents; Myasthenia Gravis; Receptor Protein-Tyrosine Kinases; Receptors, Cholinergic; Receptors, Nicotinic; T-Lymphocytes; Tacrolimus; Thymectomy; Thymoma; Thymus Gland

We examined the effect of tacrolimus on myasthenia gravis (MG). Five patients with thymoma and 5 patients without thymoma underwent prior thymectomy but showed persistent myasthenic symptoms. Oral administration with tacrolimus significantly improved MG scores 1, 3, and 6 months following the beginning of treatment in all patients (P < 0.05), and the improvement was significantly higher in the thymoma group compared with the nonthymoma group (P < 0.05). However, there was no significant change in antiacetylcholine receptor titers in either group. This indicates a particular application of immunosuppressive therapy for thymomatous MG following thymectomy.

Topics: Administration, Oral; Adult; Aged; Autoantibodies; Autoimmunity; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Receptors, Nicotinic; Tacrolimus; Thymoma; Treatment Outcome

Anti-ryanodine receptor (RyR) antibodies were measured in sera from 33 myasthenia gravis (MG) patients using three peptides from the human RyR1 sequence, two C-terminal peptides included in the functional calcium release channel, and an N-terminal peptide implicated in ion-conduction. Antibodies were more frequently positive against the two C-terminal peptides, particularly in thymoma-associated MG. In a preliminary open trial with FK506, immunosuppressant and enhancer of RyR-related sarcoplasmic calcium release, the authors observed the sustained benefits in anti-RyR-positive MG patients.

Topics: Adult; Aged; Autoantibodies; Autoantigens; Combined Modality Therapy; Enzyme-Linked Immunosorbent Assay; Epitopes; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Receptors, Cholinergic; Ryanodine Receptor Calcium Release Channel; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms; Treatment Outcome

To study the updated prevalence and clinical features of myasthenia gravis (MG) in Japan during 2017.. We sent survey sheets to the randomly selected medical departments (number = 7,545). First, we asked the number of MG patients who visited medical departments from January 1, 2017, to December 31, 2017. Then, we sent the second survey sheet to the medical departments that answered the first survey to obtain the clinical information of patients who received MG diagnosis between January 1, 2015, and December 31, 2017.. The received answer to the first survey were 2,708 (recovery rate: 35.9%). After all, the prevalence of the 100,000 population was estimated as 23.1 (95%CI: 20.5-25.6). As a result of the second survey, we obtained 1,464 case records. After checking the duplications and lacking data, we utilized 1,195 data for further analysis. The median [interquartile range (IQR)] from the onset age of total patients was 59 (43-70) years old. The male-female ratio was 1: 1.15. The onset age [median (IQR)] for female patients was 58 (40-72) years old, and that for male patients was 60 (49-69) years old (Wilcoxon-Mann-Whitney test, p = 0.0299). We divided patients into four categories: 1) anti-acetylcholine receptor antibody (AChRAb) (+) thymoma (Tm) (-), 2) AChRAb(+)Tm(+), 3) anti-muscle-specific kinase antibody (MuSKAb) (+), and AChRAb(-)MuSKAb(-) (double negative; DN). The onset age [median (IQR)] of AChRAb(+)Tm(-) was 64 (48-73) years old, and AChRb(+)Tm(+) was 55 (45-66), MuSKAb(+) was 49 (36-64), DN was 47 (35-60) year old. The multivariate logistic regression analysis using sex, initial symptoms, repetitive nerve stimulation test (RNST), and edrophonium test revealed that sex, ocular symptoms, bulbar symptoms, and RNST were factors to distinguish each category. The myasthenia gravis activities of daily living profile at the severest state were significantly higher in MuSKAb(+). MuSKAb(+) frequently received prednisolone, tacrolimus plasmapheresis, and intravenous immunoglobulin; however, they received less acetylcholine esterase inhibitor. 99.2% of AChRAb(+)Tm(+) and 15.4% of AChRAb(+)Tm(-) received thymectomy. MuSKAb(+) did not receive thymectomy, and only 5.7% of DN received thymectomy. The prognosis was favorable in all categories.. Our result revealed that the prevalence of Japanese MG doubled from the previous study using the same survey method in 2006. We also found that the onset age shifted to the elderly, and the male-female ratio reached almost even. Classification in four categories; AChRAb(+)Tm(-), AChRAb(+)Tm(+), MuSKAb(+), and DN, well describe the specific clinical features of each category and differences in therapeutic approaches.

Topics: Activities of Daily Living; Adult; Aged; Autoantibodies; Edrophonium; Esterases; Female; Humans; Immunoglobulins, Intravenous; Japan; Male; Middle Aged; Myasthenia Gravis; Prednisolone; Surveys and Questionnaires; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms

The objective was to assess which clinical factors of patients with myasthenia gravis (MG) are associated with responsiveness to calcineurin inhibitors (CNIs, cyclosporine and tacrolimus). We retrospectively analyzed the 6-month effects of CNIs in 62 MG patients. We excluded the influence of other immune treatments and determined factors associated with response to CNIs. The frequency of patients who achieved neither a > or =3-point reduction in quantitative MG score nor a > or =25% reduction in daily dose of prednisolone (poor responders) reached 35.5% (22/62) and 64.5% (40/62), respectively, compared with patients who achieved at least one of these improvements (responders). Neither dose nor blood concentration of CNIs differed between groups. Multivariate logistic regression analysis revealed time since onset of disease [odds ratio (OR) = 0.85, P = 0.005] and presence of thymoma (OR = 5.56, P = 0.05) as clinical factors that predict response to CNIs. As for MG-related autoantibody status, an autoantibody against a voltage-gated potassium channel, Kv1.4, was associated with response (OR = 9.01, P = 0.04) and showed a correlation with the presence of thymoma (P < 0.01). In MG, the early stages of disease and thymoma-associated MG are responsive to treatment with CNIs.

Topics: Adult; Aged; Autoantibodies; Calcineurin Inhibitors; Cyclosporine; Dose-Response Relationship, Drug; Female; Humans; Immunotherapy; Kv1.4 Potassium Channel; Logistic Models; Male; Middle Aged; Myasthenia Gravis; Retrospective Studies; Severity of Illness Index; Tacrolimus; Thymoma; Treatment Outcome

We examined transversely the thymus of 33 myasthenia gravis (MG) patients followed up for more than 5 years and found three thymomas. One was found 21 years after thymoma resection (Masaoka I, WHO Type B2 thymoma) and extended thymectomy. The other two were non-thymomatous at onset, and they were not treated with extended thymectomy. Therapeutic guidelines should mention the importance of follow-up in MG thymus.

Topics: Adult; Aged; Aged, 80 and over; Anti-Inflammatory Agents; Female; Humans; Immunosuppressive Agents; Longitudinal Studies; Male; Middle Aged; Myasthenia Gravis; Prednisolone; Statistics, Nonparametric; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Topics: Antineoplastic Agents, Hormonal; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Prednisolone; Tacrolimus; Thymoma; Thymus Neoplasms

To investigate whether excitation-contraction (E-C) coupling of muscle is impaired in patients with myasthenia gravis (MG).. In 51 patients with generalized MG and 35 normal subjects, compound muscle action potentials (CMAPs) of the abductor pollicis brevis, and movement-related potentials using an accelerometer placed at the thumb tip were simultaneously recorded after median nerve stimulation at the wrist. The E-C coupling time (ECCT) was estimated by a latency difference between CMAP and movement-related potential. Antibodies against acetylcholine receptor (AChR), ryanodine receptor (RyR), and muscle specific receptor tyrosine kinase (MuSK) were measured by immunoassays.. The mean ECCT was significantly longer in patients with MG (mean+/-SEM; 2.79+/-0.1 ms; p=0.002) than in normal controls (2.52+/-0.1 ms). Among MG patients, the mean ECCT was longer for patients with thymoma than for those without it (P=0.04), and was shorter for patients treated with FK506 (an immunosuppressant and also an enhancer of RyR related Ca(2+) release) than for those not receiving this treatment (p=0.04). ECCT had no significant correlation with anti-AChR, anti-RyR, or anti-MuSK antibodies.. In MG, E-C coupling appears to be impaired, particularly in patients with thymoma, and FK506 possibly facilitates E-C coupling.. The functional implication of impaired E-C coupling is not established, but it may contribute to muscle weakness in patients with MG.

Topics: Action Potentials; Adult; Aged; Electric Stimulation; Electromyography; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Intercostal Muscles; Male; Middle Aged; Muscle Contraction; Muscle, Skeletal; Myasthenia Gravis; Protein-Tyrosine Kinases; Receptors, Cholinergic; Ryanodine Receptor Calcium Release Channel; Tacrolimus; Thymoma; Thymus Neoplasms

Topics: Adult; Cyclosporine; Humans; Immunosuppressive Agents; Male; Myasthenia Gravis; Pleural Neoplasms; Red-Cell Aplasia, Pure; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms

Despite the well-known association between thymoma and PRCA, the role of thymoma remains uncertain. There is accumulating evidence that clonal T cells are involved in acquired PRCA. We examined T cell receptor repertoires in blood and thymus from a patient with PRCA associated with thymoma and myasthenia gravis. Oligoclonal expansions of Vdelta1- and Vbeta1-expressing T cells were found in peripheral blood, whereas the repertoires of Vdelta1+ and Vbeta1+ T cells in thymoma were not skewed. Oligoclonal expansion of Vdelta1-expressing T cells remained unchanged after thymectomy. Thymus may not be the site of clonal T cell expansion in thymoma-associated PRCA.

Topics: Clone Cells; Cyclosporine; Female; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Gene Rearrangement, delta-Chain T-Cell Antigen Receptor; Humans; Immunosuppressive Agents; Middle Aged; Myasthenia Gravis; Prednisolone; Red-Cell Aplasia, Pure; T-Lymphocyte Subsets; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms

A 78-year-old woman has suffered from pure red-cell aplasia (PRCA) associated with generalized myasthenia gravis and thymoma. Cyclosporin A (CyA) with corticosteroid increased numbers of erythroid cells in her bone marrow cells but she required monthly blood transfusions. Administration of tacrolimus as a substitution for CyA inhibited progression of anemia without the need for further blood transfusion. No serious side effects were observed. This case demonstrates that tacrolimus is another option of treatment for PRCA in patients who fail to respond to CyA.

Topics: Aged; Anemia; Cyclosporine; Disease Progression; Erythrocyte Transfusion; Female; Humans; Kidney; Myasthenia Gravis; Red-Cell Aplasia, Pure; Remission Induction; Tacrolimus; Thymoma

Two patients with myasthenia gravis (Ossermann IIb) involving invasive thymoma who underwent extensive thymectomy manifested myasthenic crisis shortly after the procedure; however, both patients were treated with intravenous immunoglobulin and recovered from myasthenic crisis that had been deteriorating for about 1 week. Subsequently, the patients were administered a low-dose of tacrolimus (3 mg/day) in addition to prednisolone. Several months later, tacrolimus continued to control fluctuations of myasthenic symptoms and maintained remission in these patients. The serum titer of anti-Ach-receptor antibodies decreased in parallel with clinical improvement due to tacrolimus, and we accordingly reduced the dosage of prednisolone. Tacrolimus is a new immunosuppressive agent acting through the selective inhibition of helper-T-cell activation that can be reduced dosage of steroids and can maintain remission of myasthenia gravis with invasive thymoma.

Topics: Adult; Antibodies; Antineoplastic Agents, Hormonal; Drug Interactions; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Male; Middle Aged; Myasthenia Gravis; Neoplasm Invasiveness; Prednisolone; Receptors, Cholinergic; Secondary Prevention; Tacrolimus; Thymectomy; Thymoma; Time Factors

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 73-year-old woman developed myasthenia gravis (MG) with thymoma. She had a very high level of serum antibodies against interferon-alfa (IFN-alpha). We observed the changes to her clinical symptoms and titer of the antibody during therapeutic course. Although she underwent thymectomy, intravenous methylprednisolone therapy, and oral tacrolimus administration, MG symptoms of the patient were not significantly improved and the antibody titer remained at a high level. IFN-alpha is a potent immunomodulating cytokine that regulates MHC class II expression on antigen presenting cells and activities of NK cells, B cells, and helper/suppressor T cells. This case suggests that IFN-alpha related immunological perturbation participates in the pathogenesis of thymoma-associated myasthenia gravis.

Topics: Aged; Autoantibodies; Female; Humans; Immunosuppressive Agents; Interferon-alpha; Methylprednisolone; Myasthenia Gravis; Pulse Therapy, Drug; Tacrolimus; Thymectomy; Thymoma; Thymus Neoplasms

Topics: Animals; Cell Survival; Cyclosporine; Dose-Response Relationship, Drug; Formazans; Interleukin-2; Mice; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Tetrazolium Salts; Thymoma; Time Factors; Tumor Cells, Cultured

Rapamycin, a potent immunosuppressive drug that prevents rejection of organ transplants in many animals, caused profound growth inhibition in an immature B cell lymphoma, BKS-2, at very low concentrations (2 ng/ml). Similar growth inhibition was also observed in a series of B cell lymphomas (i.e., L1.2, NFS.1.1, and WEHI-279) as well as in thymoma cells. The cell death induced by rapamycin in BKS-2 lymphoma was found to be via programmed cell death, or apoptosis. In contrast to rapamycin, neither FK506 nor CsA affected the normal growth of these cells. FK506, but not CsA antagonized the effect of rapamycin and rescued the BKS-2 cells from undergoing apoptosis. Further, suboptimal concentrations of anti-IgM antibodies and rapamycin acted synergistically in causing the growth inhibition of BKS-2 cells and this inhibitory effect was also completely reversed by FK506. Thus, rapamycin appeared to inhibit lymphoma growth by binding to FK506 binding protein. These results indicate that rapamycin should be evaluated as an effective immunosuppressive therapeutic agent to prevent the incidence of lymphoma after transplantations.

Topics: Animals; Antibiotics, Antineoplastic; Antibodies, Anti-Idiotypic; Apoptosis; B-Lymphocytes; Cell Division; Drug Screening Assays, Antitumor; Immunosuppressive Agents; Lymphoma, B-Cell; Mice; Mice, Inbred CBA; Polyenes; Sirolimus; Tacrolimus; Thymoma; Thymus Neoplasms; Tumor Cells, Cultured