Hierarchical cluster analysis based on disease-associated manifestations of patients with lymphangioleiomyomatosis: An analysis of the national database of designated intractable diseases of Japan.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disease with variable manifestations and differing rates of progression among individuals. Classification of its phenotypes is an issue for consideration. We hypothesized that clinical manifestations associated with LAM cluster together and identifying these associations would be useful for identifying phenotypes. METHODS: Using cross-sectional data from the National Database of Designated Intractable Diseases of Japan, we performed a hierarchical cluster analysis based on disease-associated manifestations. RESULTS: Four clusters were identified from 404 patients (50.4% of 801 LAM patients registered in 2016). Patients in cluster 1 had only dyspnea on exertion, relatively low lung function, the earliest onset age, and the lowest prevalence of tuberous sclerosis complex (TSC). Those in cluster 2 had various manifestations with the highest prevalence of TSC. Patients in cluster 3 had major respiratory symptoms (cough, sputum, or dyspnea on exertion) or fatigue and the lowest lung function. Those in cluster 4 were asymptomatic and had the latest onset age, shortest disease duration, and relatively high prevalence of TSC. Patients in cluster 1 had the highest rate of receiving mechanistic target of rapamycin (mTOR) inhibitor treatment, suggesting that cluster 1 included those with declining lung function for which mTOR inhibitor treatment was required. CONCLUSIONS: Hierarchical cluster analysis based on manifestations data identified four clusters. The characteristics of cluster 1 are noteworthy in relation to the indication for mTOR inhibitor treatment. A cluster analysis of accumulated and longitudinal data that allows valid clustering and outcome comparisons is required in the future.

Risk factors for stomatitis in patients with lymphangioleiomyomatosis during treatment with sirolimus: A multicenter investigator-initiated prospective study.

PURPOSE: Lymphangioleiomyomatosis is a rare lung disease caused by proliferation of abnormal smooth muscle-like cells and typically occurs in premenopausal women. Sirolimus is now the first-line drug for the treatment of lymphangioleiomyomatosis. Sirolimus-induced stomatitis is the most frequent adverse event experienced during treatment. To identify risk factors, we investigated the association of stomatitis incidence with patient background data and treatment parameters, using data from the multicenter long-term sirolimus trial. METHODS: Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5 to 15 ng/mL. The incidence of stomatitis was correlated with baseline demographics, clinical characteristics, and changes in the longitudinal data. Risk factors at baseline were assessed by using univariate and multivariate analyses. RESULTS: The most frequent adverse event was stomatitis, with the cumulative rate reaching 88.9% by 9 months, higher than that reported in postrenal transplant patients. The repetition, the duration, and the severity of stomatitis events were variable among patients. We found that patients with low hemoglobin (Hb) (<14.5 g/dL) showed significantly higher incidence than those with high Hb (≥14.5 g/dL, P < .01). The cumulative rate for stomatitis incidence was significantly associated with a decrease in the mean corpuscular volume, while the Hb level was constant; thus, red blood cell count in patients increased during the study. CONCLUSIONS: Baseline Hb levels and a decrease in mean corpuscular volume during treatment were correlated with the incidence of stomatitis.

Efficacy and Safety of Long-Term Sirolimus Therapy for Asian Patients with Lymphangioleiomyomatosis.

RATIONALE: Sirolimus has been shown in a randomized, controlled clinical trial to stabilize lung function in patients with lymphangioleiomyomatosis (LAM) treated for a 12-month time period; however the pretreatment decline in lung function after the drug was discontinued indicated that continued exposure is required to suppress disease progression. OBJECTIVES: To elucidate the durability and tolerability of long-term sirolimus treatment in Asian patients with LAM. METHODS: We conducted a single-arm, open-label, investigator-initiated safety and efficacy study of sirolimus in 63 women with LAM at 9 sites in Japan. Subjects received sirolimus for 2 years at doses adjusted to maintain a trough blood level of 5-15 ng/ml. MEASUREMENTS AND MAIN RESULTS: Fifty-two subjects (82.5%) completed the trial with mean drug compliance of more than 80% overall during the study. The number of adverse events was greatest during the initial 6 months of therapy, but they continued to occur with declining frequency throughout the 2-year study period. Of the 1,549 adverse events, 27 were classified as serious, including reversible sirolimus pneumonitis in 3 patients. New hypercholesterolemia occurred in 30 patients (48%); microcytosis in 10 patients; loss of body weight in 33 patients; and increase in blood pressure that required treatment in 5 patients. FEV1, FVC, and quality-of-life parameters were stable in the overall study cohort during the study period, but baseline to 2-year improvements in lung function occurred in the subset of patients with a prior history of chylothorax. CONCLUSIONS: Although long-term sirolimus treatment of Asian patients with LAM was associated with a large number of adverse events, including three episodes of pneumonitis, most patients completed the 2-year course of medication with good drug compliance and stable quality of life and lung function.

Reductions in pulmonary function detected in patients with lymphangioleiomyomatosis: An analysis of the Japanese National Research Project on Intractable Diseases database.

BACKGROUND: In lymphangioleiomyomatosis (LAM), predicting lung disease progression is essential for treatment planning. However, no previous Japanese studies have attempted to predict the reductions in pulmonary function that occur in LAM patients. METHODS: The data for 89 LAM patients who had undergone ≥3 spirometry tests and whose data had been registered in the Japanese National Research Project on Intractable Diseases database between October 2009 and March 2014 were analyzed after excluding patients who had undergone (1) a lung transplant; (2) mTOR inhibitor treatment; or (3) thoracic drainage, pleurodesis, surgery, or thoracic duct ligation during the study period. The rates of change (slope) in pulmonary parameters were calculated, and their associations with clinical background factors were investigated. RESULTS: Among the whole study population, the median (quartiles) slope of forced expiratory volume in one second (FEV1) was -46.7 (-95.2; -15.0)mL per year. Episodes of conservatively treated pneumothorax during the study period were found to be associated with rapid reductions in FEV1 (% predicted). Pregnancy during the study period was associated with a reduction in FEV1 (% predicted). When the patients were divided into those who exhibited initial FEV1 (% predicted) values of >70% (Group A) and ≤70% (Group B), Group B displayed significantly faster reductions in FEV1 (% predicted) than Group A. CONCLUSIONS: LAM patients whose initial FEV1 (% predicted) values are ≤70% subsequently exhibit rapid reductions in their FEV1 values, and hence, require treatment. However, the FEV1 reduction rate varies markedly among individuals and should be monitored in all cases.

[Criteria for designation of lymphangioleiomyomatosis in the Specified Disease Treatment Research Program].

Lymphangioleiomyomatosis (LAM) was added as a designated disease to the Specified Disease Treatment Research Program by the Japanese Ministry of Health, Labor, and Welfare in October 2009. This allowed patients to receive subsidies for medical expenses for its treatment. The criteria for designation, and a clinical research form into which doctors enter the diagnosis, were developed by the Respiratory Failure Research Group. These criteria were based on the LAM diagnostic criteria developed in 2005 by the same group. Computed tomographic findings of the lung and exclusion of other diseases were specified as required items. Although histological diagnosis is considered the gold standard, lung biopsy can be dangerous in some cases of advanced disease. Therefore, while histological diagnosis is recommended, diagnosis is also possible based on clinical findings. The disease was originally registered as "pulmonary LAM." However, it is now considered a systemic disease, and the name has been revised to the general term, "LAM".

The epidemiology of lymphangioleiomyomatosis in Japan: a nationwide cross-sectional study of presenting features and prognostic factors.

BACKGROUND AND OBJECTIVE: To evaluate the characteristics and prognostic factors of Japanese patients with lymphangioleiomyomatosis (LAM). METHODS: A nationwide survey to identify patients with LAM was conducted by questionnaire. Survival probability was estimated using the Kaplan-Meier method, and the prognostic factors were analysed by Cox regression. RESULTS: Data were collected on 173 patients with pulmonary LAM. The major presenting features were pneumothorax (43%) and exertional dyspnoea (37%). The survival probabilities for patients presenting with exertional dyspnoea (Group A) were 85%, 60% and 47% after 5, 10 and 15 years, respectively, and for patients presenting with pneumothorax (Group B) were 95%, 89% and 89%, respectively. Although the age at symptom onset was higher among patients in Group A than in Group B, Cox regression revealed that the presenting feature was a prognostic factor independent of age at symptom onset (Group A/B hazard ratio = 5.732, P < 0.01). In the subgroup of patients whose initial FEV(1) was >1000 mL, or FEV(1)/FVC >40%, or %DL(CO) >40%, the rate of deterioration in these tests was greater in Group A than in Group B (P < 0.01 for FEV(1), P < 0.05 for FEV(1)/FVC and %DL(CO)). CONCLUSIONS: There are two possible subgroups of LAM patients. One subgroup that presented with pneumothorax, had onset of symptoms at a younger age and a more favourable prognosis; the other presented with exertional dyspnoea, had onset of symptoms at an older age and a poorer prognosis.

Congenital solitary kidney with renovascular hypertension diagnosed by means of captopril-enhanced renography and magnetic resonance angiography.

A 24 year-old woman had a congenital solitary kidney with renovascular hypertension due to fibromuscular dysplasia. She had been treated as having essential hypertension until she developed preeclampsia and HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome at 28 weeks of gestation. Plasma renin activity and captopril test results did not indicate any abnormalities. However, renography revealed captopril-induced deterioration. Magnetic resonance angiography was also useful to detect renal artery stenosis. These findings were confirmed by renal angiography. After successful percutaneous transluminal renal angioplasty, her blood pressure and the pattern of captopril renography normalized.

Combined protein C and protein S deficiency in a family with repetitive thromboembolism and segregated gene mutations.

A young man with repetitive deep venous thrombosis of the legs and the inferior vena cava, and his family were eventually diagnosed by means of molecular genetic analysis as having both hereditary protein C and protein S deficiency. There have been a few reports of families with combined protein C and protein S deficiency and only one report of such a family characterized at the DNA level. This was the first reported family in Japan with combined deficiency of protein C and protein S accompanied by segregation of gene lesions.