May Brit Lund

Rituximab treatment of the anti-synthetase syndrome—a retrospective case series

OBJECTIVE Interstitial lung disease (ILD) is the major determinant of morbidity and mortality in the anti-synthetase syndrome (ASS). Here we have retrospectively assessed 11 ASS patients with ILD treated with the anti-CD20 mAB rituximab at our tertiary referral hospital. METHODS Data on clinical and laboratory parameters, lung imaging by high-resolution CT thorax and pulmonary function tests were collected from patient examinations done up to 6 months before rituximab was initiated, and at 3 and 6 months post-treatment. RESULTS All the 11 ASS patients had severe and progressive ILD and most of them had previously failed on cyclophosphamide and/or other immuno-modulating agents. Rituximab appeared to stabilize and/or improve the ILD in 7 of 11 ASS patients during the first 6 months after treatment. The rituximab treatment appeared to decrease the serum level of anti-Jo-1 antibodies, but the decrease was most often modest. One patient developed a fatal infection 3 months after the last infusion with rituximab. In the other ASS patients, the treatment was well tolerated. CONCLUSIONS This retrospective case series indicates a short-term beneficial effect of rituximab in ASS. Prospective, controlled studies are needed to validate this finding and further assess safety issues.

Late Medical Complications and Fatigue in Hodgkin’s Disease Survivors

PURPOSE Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkins disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkins disease (HD) may explain the high level of fatigue among HDSs. PATIENTS AND METHODS Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies. RESULTS HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P <.05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P <.01). No associations were found between cardiac sequelae or hypothyroidism and fatigue. CONCLUSION Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.

Increased risk of heart valve regurgitation after mediastinal radiation for Hodgkin's disease: an echocardiographic study.

OBJECTIVE: To assess by echocardiography the occurrence and degree of late cardiac sequelae after treatment for Hodgkins disease by radiation and chemotherapy. PATIENTS AND METHODS: In Norway from 1980 to 1988, 129 patients < 50 years old with Hodgkins disease had curative treatment with mediastinal radiation, with or without chemotherapy. 116 (90%) of these patients (mean (SD) age 37 (7) years, 67 males) were examined by echocardiography 5-13 years after treatment. 40 healthy individuals (mean (SD) age 40 (11), 20 males) were examined as controls. All those examined were in regular sinus rhythm. RESULTS: Grade > 1 (scale 0-3) aortic and/or mitral valvar regurgitation was found in 24% of the patients (15% aortic, 7% mitral, and 2% aortic+mitral), affecting 46% of the females v 16% of the males (P < 0.001). Female gender was a significant risk factor for aortic and mitral regurgitation (odds ratio 4.7, 95% confidence interval 2.0 to 11.2), whereas age, period of follow up, radiation dose, and chemotherapy were not. Thickened pericardium was diagnosed in 15% of the patients. No risk factors were identified. No cases of pericardial thickening or valvar regurgitation grade > 1 were recorded in the control group. Mean values for measured and calculated indices of systolic and diastolic function were within the normal range for patients and controls. The patients had reduced E/A ratio compared with the healthy controls (E/A 1.1 v 2.0, P < 0.001). CONCLUSIONS: Abnormal left sided valvar regurgitation was detected in one fourth of the patients, affecting the aortic valve in more than half of the cases. Females had an increased risk of valvar regurgitation. Echocardiographic screening after high-dose mediastinal radiation is recommended.

Health-Related Quality of Life in Lung Transplant Candidates and Recipients

Background: Studies on the health-related quality of life in lung transplantation have used general questionnaires, although lung-specific instruments might be more sensitive to small differences. Objectives: To compare the health-related quality of life of lung transplant recipients with lung transplant candidates, using lung-specific and general instruments, and to assess the reliability and validity of these questionnaires. Methods: The study is a cross-sectional postal survey of 31 lung transplant recipients and 15 candidates, using the following outcome measures: St. George’s Respiratory Questionnaire (SGRQ), a lung-specific health status instrument; the Short Form 36 (SF-36), a general measure, and the Hospital Anxiety and Depression scale (HAD). Results: The SGRQ showed a significantly better score (p < 0.05) for transplant recipients in the impacts and activity dimensions and the total score than for candidates. SF-36 scores showed a similar improvement in all subscales of the SF-36 except bodily pain. Cronbach’s α for all dimensions of the SGRQ, SF-36, and HAD were 0.77–0.95. Conclusions: Patients surviving lung transplantations can expect a considerable improvement in most dimensions of health-related quality of life. This finding was consistent using both lung-specific and general measures. The reliability of the questionnaires was acceptable. The associations between scales support the validity of the questionnaires in this setting.

Valvular dysfunction and left ventricular changes in Hodgkin's lymphoma survivors. A longitudinal study

Purpose:Hodgkins lymphoma survivors (HLSs) have an elevated risk for cardiovascular diseases that appear several years after radiotherapy. This study examined the time-dependent development and evolution of valvular and myocardial function related to treatment with mediastinal radiotherapy and anthracyclines in HLSs.Patients and methods:In 1993, echocardiography was performed in 116 HLSs median 10 years (range 6–13 years) after treatment with mediastinal radiotherapy. None of the 116 patients had valvular stenosis in 1993 whereas 36 (31%) had moderate valvular regurgitation. In 2005–2007, 51 of 57 invited patients were included in a second echocardiographic study – median 22 years (range 11–27 years) after treatment. Of these patients, 28 (55%) had also received anthracyclines. The patients were selected on the basis of the presence or absence of moderate valvular regurgitation in 1993.Results:The second echocardiographic study demonstrated that 10 out of 27 (37%) patients with only mild or no aortic or mitral regurgitation in 1993 had developed moderate regurgitation in either or both the aortic or mitral valve. Of the 24 patients with moderate (n=23) or severe (n=1) regurgitation in the aortic or mitral valve in 1993, 8 (33%) had progressed to severe regurgitation, developed moderate regurgitation in a previously normal or mild regurgitant valve or had received valvular replacement. In total, of all patients, 20 (39%) had developed mild to severe aortic stenosis and 3 patients had received valvular replacement. In a multiple linear regression the use of anthracyclines predicted left ventricular remodelling between ECHO 1993 and 2005 as demonstrated by increased left ventricular end systolic diameter (β =0.09 (95% CI 0.01–0.17), P=0.04) and reduced thickness of the left ventricular posterior wall (β =−0.18 (95% CI −0.33 to −0.03), P=0.02) and interventricular septum (β =−0.16 (95% CI −0.30 to −0.03), P=0.02).Conclusion:Given the progressive nature of valvular dysfunction and left ventricular remodelling 20–30 years after diagnosis, we recommend life-long cardiological follow-up of HLSs treated with mediastinal radiotherapy.

Cumulative exposure to dust causes accelerated decline in lung function in tunnel workers

OBJECTIVES To examine whether underground construction workers exposed to tunnelling pollutants over a follow up period of 8 years have an increased risk of decline in lung function and respiratory symptoms compared with reference subjects working outside the tunnel atmosphere, and relate the findings to job groups and cumulative exposure to dust and gases. METHODS 96 Tunnel workers and a reference group of 249 other heavy construction workers were examined in 1991 and re-examined in 1999. Exposure measurements were carried out to estimate personal cumulative exposure to total dust, respirable dust, α-quartz, oil mist, and nitrogen dioxide. The subjects answered a questionnaire on respiratory symptoms and smoking habits, performed spirometry, and had chest radiographs taken. Radiological signs of silicosis were evaluated (International Labour Organisation (ILO) classification). Atopy was determined by a multiple radioallergosorbent test (RAST). RESULTS The mean exposure to respirable dust and α-quartz in tunnel workers varied from 1.2–3.6 mg/m3 (respirable dust) and 0.019–0.044 mg/m3 (α-quartz) depending on job task performed. Decrease in forced expiratory volume in 1 second (FEV1) was associated with cumulative exposure to respirable dust (p<0.001) and α-quartz (p=0.02). The multiple regression model predicted that in a worker 40 years of age, the annual decrease in FEV1 would be 25 ml in a non-exposed non-smoker, 35 ml in a non-exposed smoker, and 50–63 ml in a non-smoking tunnel worker (depending on job). Compared with the reference group the odds ratio for the occurrence of new respiratory symptoms during the follow up period was increased in the tunnel workers and associated with cumulative exposure to respirable dust. CONCLUSIONS Cumulative exposures to respirable dust and α-quartz are the most important risk factors for airflow limitation in underground heavy construction workers, and cumulative exposure to respirable dust is the most important risk factor for respiratory symptoms. The finding of accelerated decline in lung function in tunnel workers suggests that better control of exposures is needed.

Increased risk of obstructive pulmonary disease in tunnel workers

BACKGROUND Tunnel workers are exposed to gases and particles from blasting and diesel exhausts. The aim of this study was to assess the occurrence of respiratory symptoms and airflow limitation in tunnel workers and to relate these findings to years of exposure. METHODS Two hundred and twelve tunnel workers and a reference group of 205 other heavy construction workers participated in a cross sectional investigation. Exposure measurements were carried out to demonstrate the difference in exposure between the two occupational groups. Spirometric tests and a questionnaire on respiratory symptoms and smoking habits were applied. Atopy was determined by a multiple radioallergosorbent test (RAST). Radiological signs of silicosis were evaluated. Respiratory symptoms and lung function were studied in relation to years of exposure and adjusted for smoking habits and atopy. RESULTS Compared with the reference subjects the tunnel workers had a significant decrease in forced vital capacity (FVC) % predicted and forced expiratory volume in one second (FEV1) % predicted when related to years of exposure. Adjusted FEV1 decreased by 17 ml for each year of tunnel work exposure compared with 0.5 ml in outdoor heavy construction workers. The tunnel workers also reported significantly higher occurrence of respiratory symptoms. The prevalence of chronic obstructive pulmonary disease (COPD) was 14% in the tunnel workers compared with 8% in the reference subjects. CONCLUSION Exposure to dust and gases from diesel exhaust, blasting, drilling and rock transport in tunnel work enhances the risk for accelerated decline in FEV1, respiratory symptoms, and COPD in tunnel workers compared with other heavy construction workers.

Carcinoid lung tumors — incidence, treatment and outcomes: a population-based study

OBJECTIVE Few published reports have examined the incidence and outcomes for patients with carcinoid lung tumors. The aim of the current study was to explore incidence, type of surgical treatment given, and outcome for patients with typical (TC) and atypical (AC) lung carcinoids in a national cohort (Norway). METHODS All lung-cancer patients diagnosed in the period 1993-2005 and who were reported to the Cancer Registry of Norway were identified. Biopsies or resection specimens were reviewed and reclassified according to the World Health Organization (WHO) 2004 classification. Surgically treated patients were staged according to the seventh edition of the pathological tumor-node-metastasis (pTNM) staging system. RESULTS Of 26665 lung cancers registered during the period, 265 (1%) had carcinoid tumors, of which 11 were diagnosed coincidentally at autopsy. In the remaining 254 patients, TCs were found in 188 cases, and ACs were found in 59 cases; seven cases had unclassifiable carcinoids. Of the 217 resected tumors, 173 (80%) were TCs. General surgeons performed 94 resections, including 11 of 17 pneumonectomies. All six bronchial resections were performed by thoracic surgeons. Of the 33 operated patients who died during follow-up, 18 had metastatic carcinoid tumors, of which 10 (56%) were ACs. In 37 non-resected patients (15 with AC and seven with unclassifiable histology), metastatic or locally advanced disease (N=21, 12 of which were ACs) was the main cause of inoperability and death. Five-year survival for all patients was 92% for TC and 66% for AC; for resected patients, the survival rates were 96% and 79%, respectively. CONCLUSIONS Carcinoids are rare malignant tumors and are, in most cases, resectable; the TC subgroup had better prognosis than the AC in univariate analyses. The main cause of death was metastasis/locally advanced tumor at presentation or recurrent disease following resection; both situations were three times more common in patients with AC.

Severe chronic obstructive pulmonary disease: Association with marginal bone loss in periodontitis

An association between chronic marginal periodontitis and chronic obstructive pulmonary disease (COPD) has been suggested. The aim of this study was to investigate whether chronic marginal periodontitis is more prevalent in very severe COPD than in other very severe respiratory diseases, and whether periodontitis in COPD is related to risk factors for periodontitis that are often present in COPD subjects. Orthopantomograms were collected from 130 patients with COPD and 50 patients with non-COPD evaluated for lung transplantation. Chronic marginal periodontitis was defined as a general marginal bone level > or = 4 mm. The prevalence of periodontitis was 44% in the COPD group vs. 7.3% in the non-COPD group. All oral measurements differed significantly between the groups. The difference in mean marginal bone level remained statistically significant when adjusting for age, gender and pack years smoked. In logistic regression analysis mean marginal bone level > or = 4 mm was identified as a factor significantly associated with severe COPD. This study demonstrates that chronic marginal periodontitis is common in patients with severe COPD. The high prevalence of periodontitis in COPD patients appears to be independent of possible risk factors for periodontitis such as age, pack years smoked, body mass index, use of corticosteroids and bone mineral density.

Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease

OBJECTIVE To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). METHODS Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). RESULTS Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). CONCLUSION This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention.