Jone Furlund Owe

Myasthenia Gravis: A Review of Available Treatment Approaches

Patients with autoimmune myasthenia gravis (MG) should be further classified before initiating therapy, as treatment response varies for ocular versus generalised, early onset versus late onset, and acetylcholine receptor antibody positive versus MuSK antibody positive disease. Most patients need immunosuppression in addition to symptomatic therapy. Prednisolone and azathioprine represent first choice drugs, whereas several second choice options are recommended and should be considered. Thymectomy should be undertaken in MG with thymoma and in generalised, early-onset MG. For MG crises and other acute exacerbations, intravenous immunoglobulin (IvIg) and plasma exchange are equally effective and safe treatments. Children and females in child bearing age need special attention regarding potential side effects of immunosuppressive therapy. MG pathogenesis is known in detail, but the immune therapy is still surprisingly unspecific, without a pin-pointed attack on the defined disease-inducing antigen-antibody reaction being available.

SEROPOSITIVE MYASTHENIA GRAVIS: A NATIONWIDE EPIDEMIOLOGIC STUDY

Few cohort epidemiologic myasthenia gravis (MG) studies have been published,1,2 most of them with data from multiple databases and varying inclusion criteria. A review from 1996 reported an increasing MG incidence and prevalence.3 Studies from the last 10 years refer to a yearly incidence between 4 and 11 per million1,2,4 and a prevalence ranging from 70 to 150 per million.1,2,4,5 There is only one laboratory in Norway offering acetylcholine receptor (AChR) antibody testing and all samples are sent to this laboratory. Presence of AChR antibodies is nearly 100% specific for MG in individuals with symptoms.6 The aims of this study were to determine the incidence and prevalence of AChR antibody-positive (seropositive) MG, to describe its gender-specific characteristics, and to examine epidemiologic trends during the last decades. ### Methods. Norway had a population of 4,737,171 inhabitants on January 1, 2008, our chosen MG prevalence day (Statistics Norway-SSB, www.ssb. no). Since the start of our AChR antibody …

Myasthenia gravis requiring pyridostigmine treatment in a national population cohort.

Background:  Pyridostigmine is the first drug of choice for patients with myasthenia gravis (MG). The drug is not prescribed regularly to any other patient groups. We aimed to determine the prevalence, incidence and gender‐specific characteristics of patients with MG needing drug treatment in a well‐defined population cohort.

Causes of death among patients with myasthenia gravis in Norway between 1951 and 2001

Objective: This study investigated the causes of death among patients with myasthenia gravis (MG), with emphasis on respiratory tract and cardiac disease. Methods: The Norwegian Cause of Death Register contains information on all deaths among Norwegian citizens. In total, 249 deceased patients with MG were identified (1951–2001). These were compared with 1245 controls deceased in the same period and matched for sex and year of birth. Results: The death certificates of patients with MG had a significantly higher occurrence of respiratory tract disease as cause of death than controls (28.1% v 20.9%, p = 0.012). The difference was most pronounced for male patients, for patients dying between 30 and 69 years of age, and for deaths occurring before 1996. For cardiac disease there was a significantly lower occurrence among patients with MG than among controls at 50–69 years of age, for both men (19.4% v 52.0%, p = 0.001) and women (14.6% v 29.6%, p = 0.036). Age and year of death were important determinants for the causes of death, but could not account for the differences between the patients with MG and controls. Conclusions: This study shows that patients with MG dying between 1951 and 1995 had a higher occurrence of respiratory tract disease listed as cause of death than had a matched control group. The lack of difference after 1995 probably reflects improved treatment of MG and its complications. The reduced occurrence of cardiac disease among patients with MG is probably explained by competing factors (respiratory tract disease) causing death.

Myasthenia gravis and risks for comorbidity.

Myasthenia gravis (MG) is an autoimmune disorder leading to skeletal muscle weakness and fatigability. MG subgroups are defined according to pathogenetic autoantibody (against acetylcholine receptor, muscle‐specific tyrosine kinase or lipoprotein receptor‐related protein 4), thymus pathology and clinical manifestations. MG patients have an increased risk for concordant autoimmune disease, in particular with early onset MG. Most common comorbidities are thyroid disease, systemic lupus erythematosus and rheumatoid arthritis. Cardiomyositis and subclinical heart dysfunction have been described in patients with thymoma MG and late onset MG but represent no major threat. A thymic lymphoepithelioma implies an increased risk for another cancer. Autoimmune MG represents no distinct cancer risk factor, although lymphomas and a few other cancer types have been reported with slightly increased frequency. Severe MG‐related muscle weakness means a risk for respiratory failure and respiratory tract infection. Drug MG treatment can lead to side‐effects. Thymectomy is regarded as a safe procedure both short and long term. Non‐MG‐related comorbidity represents a diagnostic and therapeutic challenge, especially in elderly patients. Diagnostic accuracy and optimal follow‐up is necessary to identify and treat all types of coexisting disease in MG.

Clinical and Serologic Parallels to APS-I in Patients with Thymomas and Autoantigen Transcripts in Their Tumors

Patients with the autoimmune polyendocrine syndrome type I (APS-I), caused by mutations in the autoimmune regulator (AIRE) gene, and myasthenia gravis (MG) with thymoma, show intriguing but unexplained parallels. They include uncommon manifestations like autoimmune adrenal insufficiency (AI), hypoparathyroidism, and chronic mucocutaneous candidiasis plus autoantibodies neutralizing IL-17, IL-22, and type I IFNs. Thymopoiesis in the absence of AIRE is implicated in both syndromes. To test whether these parallels extend further, we screened 247 patients with MG, thymoma, or both for clinical features and organ-specific autoantibodies characteristic of APS-I patients, and we assayed 26 thymoma samples for transcripts for AIRE and 16 peripheral tissue-specific autoantigens (TSAgs) by quantitative PCR. We found APS-I–typical autoantibodies and clinical manifestations, including chronic mucocutaneous candidiasis, AI, and asplenia, respectively, in 49 of 121 (40%) and 10 of 121 (8%) thymoma patients, but clinical features seldom occurred together with the corresponding autoantibodies. Both were rare in other MG subgroups (n = 126). In 38 patients with APS-I, by contrast, we observed neither autoantibodies against muscle Ags nor any neuromuscular disorders. Whereas relative transcript levels for AIRE and 7 of 16 TSAgs showed the expected underexpression in thymomas, levels were increased for four of the five TSAgs most frequently targeted by these patients’ autoantibodies. Therefore, the clinical and serologic parallels to APS-I in patients with thymomas are not explained purely by deficient TSAg transcription in these aberrant AIRE-deficient tumors. We therefore propose additional explanations for the unusual autoimmune biases they provoke. Thymoma patients should be monitored for potentially life-threatening APS-I manifestations such as AI and hypoparathyroidism.

Extrathymic malignancies in thymoma patients with and without myasthenia gravis

OBJECTIVE The influence of myasthenia gravis (MG) on risk of cancer is uncertain. Using nationwide, comprehensive data, we investigated the association between MG and occurrence of extrathymic malignancies in thymoma patients, and also assessed the risk of consecutive extrathymic malignancies after thymoma diagnosis. METHODS Two hundred twelve thymoma patients were identified at the Cancer Registry of Norway between 1969 and 2005. Records on all extrathymic malignancies for these patients were supplied from the Registrys database. Comparisons were made between MG and non-MG patients and between thymoma patients and the general population. RESULTS The frequency of extrathymic malignancies was similar in MG and non-MG thymoma patients, and so was the survival after thymoma diagnosis. Extrathymic malignancies occurred in 10% of thymoma patients within 10 years following the thymoma diagnosis. Thymoma patients had a significantly increased risk of developing an extrathymic malignancy compared to the general population. This was not linked to any specific kind of cancer. Thymoma morphology was not a significant predictor for an increased risk of consecutive cancer. CONCLUSIONS The immunological process underlying MG does not influence the risk of cancer in thymoma patients. Thymoma patients have a significantly increased risk of extrathymic malignancies. This is an intrinsic effect, being unaffected by a coexisting autoimmune disease such as MG and not specific for any type of cancer. Screening for extrathymic malignancies in thymoma patients is probably not recommendable, but clinicians should be aware of the high rate of extrathymic malignancies occurring in thymoma patients.

Multiple antibody detection in ‘seronegative’ myasthenia gravis patients

Myasthenia gravis (MG) is an autoimmune disease caused by antibody mediated impairment in the neuromuscular junction. Seronegative MG (SNMG) without antibodies against acetylcholine receptor (AChR) and muscle‐specific kinase (MuSK) by routine assays accounts for about 20% of all MG patients.

Left ventricular long-axis function in myasthenia gravis

Myasthenia gravis (MG) primarily affects skeletal muscles, but influence on cardiac function has been suggested. The aim of this study was to assess left ventricular long-axis function in MG patients compared to healthy controls, and to examine whether any MG-related heart involvement was influenced by the acetylcholine-esterase inhibitor pyridostigmine. We found that early diastolic atrioventricular-plane velocity and tissue Doppler peak systolic strain was lower in MG patients than in controls before pyridostigmine. The differences disappeared following administration of pyridostigmine. Also, tissue velocities at systole and early diastole tended to be lower in patients before pyridostigmine. In multivariate analyses adjusting for between-group differences in blood pressure, MG was no longer associated with lower longaxis function. Conventional echocardiographic measures of left ventricular diastolic and systolic function did not differ between groups. In conclusion, this study, using modern tissue Doppler imaging as well as conventional echocardiography, could not demonstrate definite MG-related cardiac involvement in a group of MG patients without known cardiac disease, but indicates that pyridostigmine-responsive MG-related alterations in cardiac muscle function exist in MG patients.

Radioligand-Binding Assay Reveals Distinct Autoantibody Preferences for Type I Interferons in APS I and Myasthenia Gravis Subgroups

Patients with autoimmune polyendocrine syndrome type I (APS I) or acquired thymoma-associated myasthenia gravis (MG) surprisingly share several common features, including defective expression of the transcription factor AIRE and autoantibodies against type I interferons. Here, we have adapted and validated the radioligand-binding assay we recently developed against 35S-Met-interferon-ω, for rapid and specific screening for autoantibodies against interferons-α2 and -α8. We then investigated their potential for diagnosis and for predicting clinical manifestations in patients with APS I and different subgroups of MG. Autoantibodies against interferons-ω, -α2, and -α8 occurred more often in patients with APS I (100%) and MG with thymoma (73%) than in late-onset MG (39%) and early-onset MG (5%). These autoantibodies showed preferences for interferon-ω in APS I and for the interferon-αs in MG, hinting at thymic aberrations in both groups. The exact profile of type I interferon antibodies may indicate MG subtype and may hint at thymoma recurrence.