Assessment of serum markers KL-6 and SP-D for interstitial pneumonia associated with connective tissue diseases]

There are a lot of difficulties in the estimation of interstitial pneumonia and subsequent pulmonary fibrosis associated with connective tissue diseases. Recently, serum KL-6 (KL-6) and serum surfactant protein D (SP-D) have been reported to be useful to estimate the severity of interstitial pneumonia. We investigated the usefulness of these serum markers comparing to the spirometric parameters in patients with interstitial pneumonia associated with connective tissue diseases. We found significant inverse correlation between KL-6 and spirometric % VC. Furthermore, KL-6 was more significantly inverse-related with %DLco. On the other hand, we found neither correlation between SP-D and %VC, nor between SP-D and %DLco, suggesting SP-D level seems to be not affected by the degree of pulmonary fibrosis itself. These results indicate that KL-6 is useful to estimate the severity of pulmonary fibrosis more precisely than SP-D in patients with interstitial pneumonia associated with connective tissue diseases.     

A case of Farmer's lung accompaign with caseous granuloma, monitored with serum KL-6 and SP-D]

A 65-year-old man was admitted to our hospital with a productive cough, fever, and dyspnea; his chest radiographs revealed diffuse nodular and ground-glass opacities. He had worked on a farm for 11 years. Six months earlier, he had presented with similar symptoms at another hospital, and was admitted with suspected atypical pneumonia. After treatment with antibiotics, his condition improved and he was discharged. Examination on admission to our hospital revealed markedly elevated serum KL-6 levels. Histological findings from specimens obtained by video-assisted thoracic surgical lung biopsy showed caseating and non-caseating epitheloid cell granuloma, lymphocyte infiltration, and alveolitis. Bacteriological tests for mycobacteria and fungi were all negative. Farmer's lung was diagnosed in accordance with the criteria for hypersensitive pneumonia. It is generally accepted that the distinguishing histological finding for Farmer's lung disease is non-caseating epitheloid cell granuloma, but in this case, caseous granuloma was also present.     

Elevation of serum KL-6 levels in 3 patients with rheumatoid arthritis treated with adalimumab

Abstract

We describe 3 cases of rheumatoid arthritis presenting with elevated serum KL-6 levels during treatment with adalimumab, which was discontinued because of suspected onset of complications. However, no complications were observed following discontinuation despite comprehensive assessments, and KL-6 levels subsequently returned to baseline levels. In our institutes, 3 out of 29 cases treated with adalimumab showed elevated KL-6 levels. The baseline levels were 445, 347, and 547 U/ml, while the peak levels were 1010, 546, and 2007 U/ml, respectively. The elevated KL-6 levels seem to have been innocuous; nevertheless, further careful observation is deemed necessary.     

Elevation of serum KL-6 levels in 3 patients with rheumatoid arthritis treated with adalimumab

We describe 3 cases of rheumatoid arthritis presenting with elevated serum KL-6 levels during treatment with adalimumab, which was discontinued because of suspected onset of complications. However, no complications were observed following discontinuation despite comprehensive assessments, and KL-6 levels subsequently returned to baseline levels. In our institutes, 3 out of 29 cases treated with adalimumab showed elevated KL-6 levels. The baseline levels were 445, 347, and 547 U/ml, while the peak levels were 1010, 546, and 2007 U/ml, respectively. The elevated KL-6 levels seem to have been innocuous; nevertheless, further careful observation is deemed necessary.     

High serum KL-6 levels predict the deterioration of pulmonary function in patients with rheumatoid arthritis

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced (P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.     

High serum KL-6 levels predict the deterioration of pulmonary function in patients with rheumatoid arthritis

Abstract

KL-6 has been reported to be a serum marker for interstitial pneumonitis (IP). The purpose of this study was to determine the predictive value of KL-6 on the deterioration of vital capacity (VC) in rheumatoid arthritis (RA) patients with IP. In 32 RA patients we evaluated both the serum KL-6 level and VC in a prospective design. The diagnosis of IP was determined by clinical symptoms, chest X-ray, high-resolution computed tomography (HRCT) scanning and/or pulmonary function tests. Findings such as reticulonodular and/or cystic shadows on HRCT scanning were accepted as IP signs. The IP signs with ground-glass opacity were set as active. The mean period of observation was 31.2 (5.6) months. The initial and/or final serum KL-6 levels were more than 520 U/ml in seven patients (H-KL group). In the other 25 patients, both the initial and final KL-6 levels were 520 U/ml or less (L-KL group). Among the H-KL group patients, their percent VC (%VC) was significantly reduced ( P < 0.01) during the observation period. No significant changes of KL-6 and %VC levels were seen in the L-KL group. Thus, we conclude that in RA patients with IP, abnormal levels of serum KL-6 may predict the deterioration of VC.     

A case of chronic hypersensitivity pneumonia with elevation of serum SP-D and KL-6]

A 73-year-old woman suffering from dyspnea on effort and chronic cough was admitted to our hospital. Chest computed tomography disclosed ground-glass opacities, irregular linear opacities and honeycombing distributed predominantly in the subpleural area. The serum levels of SP-D and KL-6 rose to 889 ng/ml, 1,755 U/ml, respectively. These findings indicated idiopathic pulmonary fibrosis. However, the number of lymphocytes and the CD4/CD8 ratio in the BAL fluid were elevated. Transbronchial lung biopsy specimens demonstrated alveolitis with granuloma formation. The evidence that she had lived in a house with a heavy fungal growth and that tests of precipitation in response to Penicillium corylophilum were positive confirmations of a diagnosis of chronic hypersensitivity pneumonia.     

A case of severe Legionella pneumonia monitored with serum SP-A, SP-D, and KL-6]

A 67-year-old man was admitted for acute pneumonia on July 20th, 1999. Chest radiographs disclosed dense consolidation in the right lower lung fields. After admission, the pneumonia underwent rapid advance. On the basis of serological findings and cultures of pleural effusion and sputum, the patient was given a diagnosis of acute pneumonia caused by Legionella pneumophila 1 a. He gradually recovered from the pneumonia by means of chemotherapy using EM, RFP, Mino, gammaglobulins and steroids. The serum SP-A, SP-D, and KL-6 peaked on July 23rd, July 30th, and August 12th, respectively.     

Clinical significance of serum KL-6 and SP-D for the diagnosis and treatment of interstitial lung disease in patients with diffuse connective tissue disorders]

OBJECTIVE: To elucidate the clinical significance of serum KL-6 and SP-D for the diagnosis and treatment of interstitial lung disease in connective tissue disorders. METHODS: 139 patients with various connective tissue disorders were subjected for the study, which included 46 cases of rheumatoid arthritis, 43 cases of Sj?gren's syndrome, 16 cases of SLE, 10 cases of systemic sclerosis, 9 cases of polymyositis/dermatomyositis, 6 cases of vasculitis syndrome, 5 cases of Beh?et's disease and 4 cases of MCTD. Serum levels of KL-6 and SP-D were determined by enzyme-immunoassay. The sensitivity, specificity and accuracy of serum KL-6 and SP-D for the diagnosis of interstitial lung disease were compared with serum LDH. The relationship of serum KL-6 and SP-D levels with high resolution CT (HRCT) of the lung and Gallium scintigraphy findings was analyzed. In some cases, serum levels of the two markers were determined monthly in the course of the disease. RESULTS: When the serum levels of KL-6 and SP-D were measured simultaneously, the sensitivity to diagnose interstitial lung disease was 67.7%, the specificity was 98.1%, and the accuracy was 91.4%, while those of serum LDH were 45.2%, 88.9%, 79.1% respectively. In the patients with interstitial lung disease, those who had elevated serum levels of both KL-6 and SP-D showed parenchymal collapse opacity-dominant pattern in HRCT. On the other hand, the patients with interstitial lung disease who had normal levels of serum KL-6 and SP-D or had elevation either in KL-6 or SP-D levels showed ground glass opacity-dominant pattern in HRCT. There was no significant correlation between serum marker levels and Gallium scintigraphy findings. When serum KL-6 and SP-D were measured monthly, the levels of both markers changed more specifically and sensitively to the lung disease activity compared with serum LDH. CONCLUSIONS: Serum KL-6 and SP-D are more specific and useful markers for the diagnosis and evaluation of interstitial lung disease compared with serum LDH in connective tissue disorders.     

Clinical,laboratory, radiographic,and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis. A multicenter study with literature review

Objective. To describe the clinical, laboratory, radiologic, and histopathologic features of methotrexate (MTX)-induced lung injury in a combined cohort of selected patients with rheumatoid arthritis (RA) and all cases reported in the English-language literature. Methods. Retrospective combined cohort review and abstraction from the medical literature. Case reports were obtained from 6 centers that had 4 or more cases of potential MTX lung injury per site. RA patients who were seen between 1981 and 1993 and who satisfied predetermined criteria for the presence of MTX lung injury were identified. Results. Twenty-seven patients satisfied the criteria for definite MTX lung injury, and 2 for probable MTX lung injury. Predominant clinical features of MTX lung injury included shortness of breath in 27 patients (93.1%), which was present for 23.5 ± 22.3 days (mean ± SD), cough in 24 (82.8%), present for 26.9 ± 28.5 days, and fever in 20 (69.0%), present for 10.4 ± 12.8 days. Five patients (17.2%) died, compared with 12 of 68 (17.6%) reported in the medical literature. Four of the 6 patients who were re-treated with MTX after an initial pulmonary event developed recurrent lung toxicity, resulting in 2 deaths, compared with a recurrence rate of 3 of 6 in the literature. Conclusion. MTX lung injury is most often a subacute process, in which symptoms are commonly present for several weeks before diagnosis. Approximately 50% of the cases are diagnosed within 32 weeks from initiation of MTX treatment. A patient who recovers from MTX lung injury should not be re-treated. Earlier recognition and drug withdrawal may avoid the serious and sometimes fatal outcome that has been observed in this and other studies.     

Circadian rhythm of serum interleukin-6 in rheumatoid arthritis.

OBJECTIVES--To test the hypothesis of a diurnal variation in circulating levels of interleukin-6 (IL-6) and/or tumour necrosis factor-alpha (TNF-alpha) in rheumatoid arthritis and other inflammatory connective tissue diseases. METHODS--Serum levels of IL-6 and TNF-alpha were measured at three hour intervals from 7:30 to 22:30 in 48 patients with different rheumatic diseases as well as ten healthy controls. In four of the patients with rheumatoid arthritis, serum IL-6 levels were measured before and after one week of treatment with prednisolone 15-20 mg daily. RESULTS--IL-6 and TNF-alpha could not be detected in serum from healthy controls. However, serum IL-6 levels were substantially increased in patients with rheumatoid arthritis. Furthermore, patients with rheumatoid arthritis showed a statistically significant circadian variation in levels of IL-6. Peak values appeared in the morning and low values in the afternoon and evening. In contrast, levels were low and stable in other connective tissue diseases. Levels of TNF-alpha were low in patients with rheumatoid arthritis and high in patients with other connective tissue diseases, but without circadian rhythm. After treatment with prednisolone, levels of serum IL-6 decreased significantly, but the circadian rhythm remained. CONCLUSIONS--The circadian rhythm of circulating IL-6 might correspond to the circadian rhythm of symptoms in rheumatoid arthritis. The diurnal variation of IL-6, and possibly other cytokines, might explain the conflicting results previously reported on the inter-relationship between circulating IL-6 levels and disease activity in rheumatoid arthritis.     

类风湿关节炎合并间质性肺病患者血清表面活性蛋白A和D水平及临床意义

目的 探讨类风湿关节炎(RA)合并间质性肺病(ILD)患者的血清表面活性蛋白A(SP-A)和D(SP-D)水平及临床意义.方法 采用双抗体夹心酶联免疫吸附试验(ELISA)法检测SP-A和SP-D,并比较单纯RA组、RA-ILD组、对照组血清样本SPA和SP-D水平的差异,分析其与RA合并ILD的相关性.计算3组血清SP-A和SP-D阳性检出率.分析SP-A和SP-D与年龄、红细胞沉降率(ESR)、C反应蛋白(CRP)、类风湿因子(RF)、抗环瓜氨酸肽(CCP)抗体、抗核抗体、抗核周因子(APF)和抗角蛋白抗体(AKA)之间的相关性.多组间均数的比较采用方差分析,数据间的相关性分析采用Spearman等级相关.结果 ①RA-ILD组、单纯RA组、对照组的血清SP-A水平分别为(51.2±9.2)、(25.9±2.6)、(15.4±0.3)μg/L,SP-D水平分别为(42.5±8.1)、(20.8±1.5)、(16.6±0.8)μg/L.RA-ILD组患者血清SP-A和SP-D水平高于单纯RA组以及对照组(P＜0.05).单纯RA组患者血清SP-A和SP-D水平和健康对照组比较差异无统计学意义(P＞0.05).②RA-ILD组血清SP-A和SP-D的阳性率明显高于单纯RA组(x2=5.21,P=0.02;x2=4.79,P=0.01)和健康对照组(x2=4.96,P=0.03;x2=4.75,P=0.02),RA-ILD组血清SP-D的阳性检出率大于血清SP-A(x2=4.95,P=0.04).③RA-ILD患者血清SP-A、SP-D水平与年龄、CRP呈正相关(r=0.687,P=0.001;r=0.571,P=0.009).④RA-ILD患者血清SP-D水平与RF、抗CCP抗体和AKA呈正相关,而血清SP-A、SP-D水平与抗核抗体、APF、ESR无相关性.结论 ①SP-A和SP-D可作为RA合并ILD的血清学标志;②SP-A和SP-D在早期诊断RA合并ILD方面有一定价值,SP-D更有效地提示RA合并ILD存在,判断肺损伤程度,预测疾病转归情况.     

Pulmonary and retroperitoneal lesions induced by methotrexate-associated lymphoproliferative disorder in a patient with rheumatoid arthritis

A 78-year-old man had fatigue and appetite loss for 5 months. He had been receiving low-dose methotrexate for rheumatoid arthritis. Computed tomography revealed multiple pulmonary infiltrations and muddiness of the fatty tissue surrounding the right kidney, ureter wall thickening, and hydroureter/nephrosis, which were suspected retroperitoneal fibrosis. Lung biopsy revealed polymorphic/lymphoplasmacytic lymphoproliferative disorder. Methotrexate withdrawal resulted in spontaneous regression. Therefore, retroperitoneal lesion may account for the diagnosis as having retroperitoneal lymphoproliferative disorder, not retroperitoneal fibrosis.     

Multiplex serum cytokine monitoring as a prognostic tool in rheumatoid arthritis

OBJECTIVE: Early optimized therapy of rheumatoid arthritis (RA) results in improved outcomes. The initiation of optimized therapy is hindered by the difficulty of early diagnosis and the limitations of current disease activity and therapeutic response assessment tools. Identifying patients requiring early combination DMARD/biologic therapy is currently a significant clinical challenge given the lack of definitive prognostic criteria. Since cytokines are soluble intracellular signaling molecules that modulate disease pathology in RA, we tested the recent conjecture that en mass serum cyto-kine measurement and monitoring will provide a useful tool for effective therapeutic management in RA. METHODS: We assayed the levels of 16 serum cytokines in 18 RA patients treated prospectively with methotrexate and from 18 unaffected controls. Specific mechanistic aspects of inflammatory pathology in the periphery could be discerned on a patient-specific basis from patients' serum cytokine profiles, information that may aid in the design of anti-cytokine biologic therapy. A serum Cytokine Activity Index (CAI) was also created using multi-variant analysis methods. RESULTS: Distinct cytokines were significantly elevated in RA patients relative to controls, and three distinct clusters with correlations to disease activity were identified. The Cytokine Activity Index correlated well with the therapeutic res-ponse; responders and non-responders in this cohort were distinguishable as early as one month post initiation of methotrexate therapy, well before clinical assessments of response are commonly completed. CONCLUSION: Clinical assessment tools could be derived from this approach that may provide a means to continually track patients, allowing intervention strategies to be better evaluated on a patient-specific basis and to identify residual cytokine activity that could be used to guide combination therapy.     

Comparative study of serum surfactant protein-D and KL-6 concentrations in patients with systemic sclerosis as markers for monitoring the activity of pulmonary fibrosis

OBJECTIVE: To clarify the clinical significance of surfactant protein-D (SP-D) and KL-6 in the diagnosis and monitoring of pulmonary fibrosis (PF) in patients with systemic sclerosis (SSc), and to evaluate the differences between SP-D and KL-6. METHODS: Serum SP-D and KL-6 concentrations were determined by ELISA in 42 SSc patients. In a retrospective longitudinal study, 83 serum samples from 6 SSc patients were analyzed during a followup period of 0.6-6.3 years. RESULTS: SP-D and KL-6 concentrations at the first visit were higher in patients with SSc, especially those with PF, compared with healthy controls. Increased concentrations of SP-D were associated with decreased DLCO and decreased vital capacity in SSc patients more strongly than those of KL-6. The sensitivity and specificity for PF were 91% and 88% for SP-D and 39% and 100% for KL-6, respectively. In the longitudinal study, both SP-D and KL-6 concentrations were associated with activity of PF in patients with SSc. SP-D concentrations changed more rapidly than KL-6 concentrations, in parallel with the PF activity. CONCLUSION: SP-D was a more sensitive marker for PF than KL-6. By contrast, KL-6 showed higher specificity than SP-D. Combined use of these 2 serum markers would be more helpful to diagnose and monitor the PF activity in patients with SSc than single use of each marker.     

Controlled trial of clinical utility of serum salicylate monitoring in rheumatoid arthritis

A crossover double-blind controlled trial was performed on 36 patients with rheumatoid arthritis to assess the necessity for serum salicylate monitoring in determining optimal dosage. There was no clinically or statistically significant increase in the clinical improvement of patients associated with serum monitoring but potentially toxic serum levels occurred without tinnitus when serum monitoring was not used.     

Leflunomide-related lung injury in patients with rheumatoid arthritis: imaging features

Imaging findings of 26 cases of leflunomide (Arava)-related acute lung injury were analyzed. Thirteen cases had pre-existing interstitial pulmonary disease on chest X-ray or computed tomography. The main features of clinically determined leflunomide-induced acute lung injury were similar to those caused by other drugs: diffuse or widespread patchy ground-glass opacities and/or consolidation, frequently accompanied by septal thickening and intralobular reticular opacities. We categorized these findings into four patterns: diffuse alveolar damage (DAD), acute eosinophilic pneumonia, hyperreaction, and cryptogenic organizing pneumonia. The DAD group had a higher mortality rate, but statistically not a significant one. It is impossible to exclude infectious disease such as pneumocystis carinii pneumonia based on imaging findings, and detailed correlation of imaging findings with clinical and laboratory findings is essential in order to make a correct diagnosis.