Mortality in rheumatoid arthritis patients with pulmonary nontuberculous mycobacterial disease: A retrospective cohort study.

OBJECTIVE: The aim of this study was to compare long-term mortality following diagnosis of pulmonary nontuberculous mycobacterial (NTM) disease between patients with and without rheumatoid arthritis (RA) and to evaluate predictive factors for death outcomes. METHODS: We reviewed the electronic medical records of all patients who were newly diagnosed with pulmonary NTM disease at participating institutions between August 2009 and December 2018. Patients were followed until death, loss to follow-up, or the end of the study. Taking into consideration the presence of competing risks, we used the cumulative incidence function with Gray's test and Fine-Gray regression analysis for survival analysis. RESULTS: A total of 225 patients (34 RA patients and 191 non-RA controls) were followed, with a mean time of 47.5 months. Death occurred in 35.3% of RA patients and 25.7% of non-RA patients. An exacerbation of pulmonary NTM disease represented the major cause of death. The estimated cumulative incidence of all-cause death at 5 years was 24% for RA patients and 23% for non-RA patients. For NTM-related death, the 5-year cumulative incidence rate was estimated to be 11% for RA patients and 18% for non-RA patients. Gray's test revealed that long-term mortality estimates were not significantly different between patient groups. Fine-Gray regression analysis showed that the predictive factors for NTM-related death were advanced age (adjusted hazards ratio 7.28 [95% confidence interval 2.91-18.20] for ≥80 years and 3.68 [1.46-9.26] for 70-80 years vs. <70 years), male sex (2.40 [1.29-4.45]), Mycobacterium abscessus complex (4.30 [1.46-12.69] vs. M. avium), and cavitary disease (4.08 [1.70-9.80]). CONCLUSIONS: RA patients with pulmonary NTM disease were not at greater risk of long-term mortality compared with non-RA patients. Rather, advanced age, male sex, causative NTM species, and cavitary NTM disease should be considered when predicting the outcomes of RA patients with pulmonary NTM disease.

Glucocorticoid-resistant polymyalgia rheumatica: pretreatment characteristics and tocilizumab therapy.

Treatment with glucocorticoid (GC) is the preferred therapy for polymyalgia rheumatica (PMR), but some patients show poor responses to the initial GC regimen or experience flares on GC tapering. Alternative therapies for patients with GC resistance have not yet been established. To evaluate pretreatment characteristics and therapeutic outcomes of GC-resistant PMR, we followed all patients who had been diagnosed with PMR between October 2007 and February 2013, according to our standardized protocol. GC-resistant patients were defined as those who had responded poorly to the initial GC regimen (15 mg/day of prednisolone) or those who had responded to the initial regimen but had experienced a flare upon GC tapering to 5 mg/day of the maintenance dose or within the first 6 months of maintenance therapy. Out of 23 patients, nine were found to be GC-resistant cases and the others were GC responders. Baseline values of PMR activity score and its components, especially the ability to elevate the upper limbs (EUL), were significantly higher in GC-resistant patients compared with GC responders. The additional use of methotrexate (MTX, five cases), salazosulfapyridine (one case), and tocilizumab (TCZ, three cases) was effective for GC-resistant patients, although 13 to 39 weeks were required for the achievement of remission. We report the three GC-resistant cases in which TCZ was added to GC therapy with or without MTX. We also review the medical literature on the use of TCZ as of January 31, 2014 and discuss the utility of TCZ in the treatment of GC-resistant PMR.

Organizing Pneumonia in Rheumatoid Arthritis Patients: A Case-Based Review.

We treated 21 patients with organizing pneumonia (OP) associated with rheumatoid arthritis (RA) or related to biological disease-modifying antirheumatic drugs (DMARDs) at our institution between 2006 and 2014. Among these cases, 3 (14.3%) preceded articular symptoms of RA, 4 (19.0%) developed simultaneously with RA onset, and 14 (66.7%) occurred during follow-up periods for RA. In the case of OP preceding RA, increased levels of anti-cyclic citrullinated peptide antibodies and rheumatoid factor were observed at the OP onset. RA disease activity was related to the development of OP in the simultaneous cases. In the cases of OP developing after RA diagnosis, 10 of 14 patients had maintained low disease activity with biological DMARD therapy at the OP onset, and among them, 6 patients developed OP within the first year of this therapy. In the remaining four patients, RA activity was not controlled at the OP onset. All patients responded well to systemic steroid therapy, but two patients suffered from relapses of articular and pulmonary symptoms upon steroid tapering. In most of the RA patients, DMARD therapy was introduced or restarted during the steroid tapering. We successfully restarted a biological DMARD that had not been previously used for patients whose RA would otherwise have been difficult to control. In this study, we also perform a review of the literature on RA-associated or biological DMARD-related OP and discuss the pathogenesis and management of OP occurring in RA patients.

Pulmonary Mycobacterium abscessus disease in a patient receiving low-dose methotrexate for treatment of early rheumatoid arthritis.

A 70-year-old woman with methotrexate (MTX)-refractory rheumatoid arthritis (RA) was referred to our hospital for introduction of biological therapy. On high-resolution computed tomography scans, the patient exhibited abnormal findings such as bronchiectasis and centrilobular small nodules, which were highly suggestive of pulmonary nontuberculous mycobacterial (NTM) disease. Although mycobacterial cultures of sputum specimens yielded negative results, cultures of bronchoalveolar lavage fluids grew Mycobacterium abscessus. Frequent follow-up chest radiographs indicated that the patient's pulmonary disease became rapidly worse in 1 month following dose escalation of MTX and administration of low-dose prednisolone. Oral clarithromycin and levofloxacin, chosen on the basis of in vitro susceptibility testing, led to a dramatic recovery from this potentially life-threatening complication. Through our experience with this case, we have learned that (1) pulmonary M. abscessus disease can progress rapidly, even during nonbiological anti-RA therapy; (2) regular follow-up chest radiographs are useful to ensure timely implementation of anti-NTM treatment; (3) bronchoscopic testing should be considered when patients are suspected of pulmonary NTM disease but do not meet the diagnostic criteria; and (4) early isolation, identification, and susceptibility testing of causative NTM species are critical for favorable outcomes.

Polyvinyl alcohol-based hydrogel dressing gellable on-wound via a co-enzymatic reaction triggered by glucose in the wound exudate.

Glucose is a common component of body fluids. We describe a hydrogel wound dressing that can be obtained by pouring an aqueous solution of a polyvinyl alcohol derivative possessing phenolic hydroxyl moieties (PVA-Ph), containing glucose oxidase (GOx) and horseradish peroxidase (HRP), onto a wound. The in situ hydrogelation progresses through GOx-catalysed hydrogen peroxide (H2O2) generation from glucose in the wound exudate and HRP-catalysed cross-linking between phenolic hydroxyl moieties in PVA-Ph by consuming the H2O2. The potency as a wound dressing is demonstrated by experiments which reveal that the existence of the conditions inducing hydrogelation within 20 s at normal blood glucose concentration, the durability of the resultant hydrogels to compression and stretching, and the faster closure of full-thickness wounds created on rats treated with the in situ formed hydrogel than those treated by a commercially available hydrogel dressing.

Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis.

OBJECTIVE: To identify clinical and genetic risk factors for interstitial lung disease (ILD) or airway disease (AD) in patients with rheumatoid arthritis (RA) and to evaluate differences between the associations of these factors with ILD and AD. METHODS: We reviewed high-resolution computed tomography (HRCT) images and clinical data of 356 RA patients obtained at their first visit. The diagnosis of ILD and AD was based on abnormal HRCT findings. Multinomial logistic regression analysis and likelihood ratio tests were performed. RESULTS: High titers of rheumatoid factor are similarly associated with increased risks of ILD (relative risk ratio, 3.1; p = 0.02) and AD (relative risk ratio, 3.0; p = 0.02). High levels of anti-cyclic citrullinated peptide antibodies were associated strongly with AD (relative risk ratio, 3.8; p = 0.005) and less strongly with ILD (relative risk ratio, 2.7; p = 0.07). Age was the potent risk factor for ILD (relative risk ratio, 4.6; p = 0.003), while that for AD was advanced stage (relative risk ratio, 11.5; p < 0.0005). The carriage of HLA-DRB1*1502 had opposite influences on the two conditions: relative risk ratio = 4.02 for ILD (p = 0.013) and relative risk ratio = 0.15 for AD (p = 0.08). This difference was statistically significant (p = 0.0005). Associations of sex and smoking history with ILD disappeared in the multinomial logistic regression analysis. CONCLUSIONS: The differential associations of ILD and AD with various clinical and genetic factors suggest that ILD and AD have distinct etiologies in RA.

Small airway obstruction in patients with rheumatoid arthritis.

This work was intended to evaluate the prevalence of obstructive small-airway disease in patients with rheumatoid arthritis (RA) and its association with clinical characteristics. Pulmonary function testing (PFT) and high-resolution computed tomography (HRCT) were performed on 189 consecutive RA patients. Each case was diagnosed based on abnormal HRCT findings. We defined obstructive dysfunction of small airways as a forced expiratory flow from 25% to 75% of vital capacity (FEF(25-75)) value >1.96 residual standard deviation (RSD) below predicted values. We found 19 patients (10.1%) with an interstitial pneumonia (IP) pattern and 15 (7.9%) with a bronchiolitis pattern; the other 155 (82.0%) had no abnormal HRCT patterns. In patients with neither abnormal pattern, median values of percentage predicted for carbon monoxide diffusing capacity (DL(CO)) and ratio of DL(CO) to alveolar ventilation (DLco/VA) were within the normal range, but median FEF(25-75), forced expiratory flow at 25% of vital capacity (V(25)), and V(25)/height were <70% of predicted values. Forty-seven patients (30.3%) in this group had obstructive small-airway dysfunction. Multivariate logistic regression analysis indicated that this type of abnormality is strongly associated with respiratory symptoms [odds ratio (OR) 5.18; 95% confidence interval (CI) 1.70-15.75; p = 0.012), smoking history (OR 2.78; 95% CI 1.10-6.99; p = 0.03), and disease duration >10 years (OR 2.86; 95% CI 1.27-6.48; p = 0.012). Parenchymal micronodules, bronchial-wall thickening, and bronchial dilatation on HRCT scans were also predictive factors for abnormal FEF(25-75), although these morphological changes were too limited for us to diagnose these patients with the bronchiolitis pattern. Obstructive dysfunction of small airways is apparently common among RA patients, even among those with neither the IP nor the bronchiolitis pattern on HRCT scans. Factors significantly associated with abnormal FEF(25-75) are respiratory symptoms, smoking history, and RA duration.

Comparison of pulmonary abnormalities on high-resolution computed tomography in patients with early versus longstanding rheumatoid arthritis.

OBJECTIVE: To identify the predominant radiological abnormalities in the lungs of patients with early rheumatoid arthritis (RA) and in those with longstanding RA. METHODS: We performed high-resolution computed tomography (HRCT) on a total of 126 patients with early RA (n = 65) and longstanding RA (n = 61). The most likely diagnosis for each case was made on the basis of the predominant HRCT findings and their extent in the lungs. Pulmonary function tests were done for RA patients with parenchymal abnormalities. RESULTS: The most frequent finding was bronchial dilatation (41.3%), followed by ground-glass attenuation (27.0%), parenchymal micronodules (15.1%), subpleural micronodules (15.1%), reticulation (11.9%), bronchial wall thickening (11.9%), nodules (10.3%), honeycombing (8.7%), and airspace consolidation (4%). Parenchymal micronodules and bronchial wall thickening, indicative of small airway diseases, were more prominent in the patients with longstanding RA. There were no significant differences in the frequency of interstitial abnormalities such as ground-glass attenuation, reticulation, honeycombing, or consolidation between the 2 groups. We identified 10 patients with bronchiolitis pattern, 11 with nonspecific interstitial pneumonia (NSIP) pattern, 2 with usual interstitial pneumonia (UIP) pattern, and 2 with organizing pneumonia (OP) pattern. Mean values of FEV1/FVC ratio and FEV25-75 were lower in the patients with the bronchiolitis pattern, and DLCO was decreased in the patients with the NSIP or UIP pattern. CONCLUSION: Interstitial abnormalities were frequently observed even in patients with early RA, although most of them had no respiratory symptoms. Bronchiolar abnormalities were associated with the duration of RA.

A simultaneous onset of organizing pneumonia and rheumatoid arthritis, along with a review of the literature.

Organizing pneumonia (OP) is a specific type of interstitial pneumonia that has been noted as one of the pulmonary manifestations during the course of rheumatoid arthritis (RA). In this study, we report a case with a simultaneous development of OP and RA. The patient presented with concurrent flu-like symptoms and arthralgia of multiple joints, and antibiotic therapy was not effective. The rheumatoid factor (RF) and anti-cyclic citrullinated antibodies were both high. Multiple air-space opacities on chest radiographs and bilateral peripheral consolidations on high-resolution computed tomography films were evident. The histology of transbronchial lung biopsy samples was characterized by intra-alveolar buds of granulation tissue consisting of intermixed myofibroblasts and connective tissues. Treatment with prednisolone induced a complete recovery from OP without relapses. Our review of previous reports about RA-associated OP (RA-OP) suggested that the high titer of RF and increased disease activity of RA indicate a great risk of developing OP. This condition may represent a lung's reaction in the RA-associated inflammatory and/or immune process. We should be aware of RA-OP cases in which pulmonary manifestations precede articular symptoms. In these cases, respiratory manifestations are the main evidence of RA activity. In most cases of steroid-resistant RA-OP, the use of immunosuppressants was effective. Since OP may progress to fibrotic lung disease during the course of RA, we may consider performing a second lung biopsy for steroid-resistant patients, even if they have once been diagnosed as OP.

Early rheumatoid arthritis in a patient with Sjögren's syndrome and pulmonary nodular amyloidosis: clinical implication of early limited use of infliximab.

Infliximab, an anti-tumor necrosis factor alpha antibody, is among the most effective therapies for rheumatoid arthritis (RA). In this study, we report a patient with early RA of 6 months who has Sjögren's syndrome and pulmonary nodular lesions concomitantly. The patient did not respond to methotrexate (MTX, 6;Smg per week) for 3 months. When introduction of infliximab therapy is considered, we need to exclude the possibility of pulmonary granulomatous infection and malignancy. With the use of computed tomography-guided percutaneous needle biopsy and subsequent histological examinations, this case was rapidly and confidently diagnosed as localized pulmonary nodular amyloidosis. Immunochemical staining showed light chain type nodular amyloidosis by a deposition of immunoglobulin kappa light chains, which is a rare condition in a patient with Sjögren's syndrome. We started combination therapy of infliximab (200;Smg per infusion) and MTX (6;Smg per week). Because of severe systemic eruption, this therapy was stopped halfway through the third infusion of infliximab, and MTX monotherapy was continued. Despite the withdrawal of infliximab therapy, the C-reactive protein values were decreased to an undetectable level at week 14, and the disease activity score for 28 joints was 3.1 at week 22. Clinical remission has been maintained more than 14 months with MTX alone. Infliximab has been used only for patients with recalcitrant RA, because the cost of its lifelong use would be an economic burden in most cases. An optimal and affordable strategy for the treatment of early RA should be developed. Our findings may support the idea that the combination therapy of infliximab and MTX for early RA alters the course of the disease.

Clinical characteristics of polymyalgia rheumatica in Japanese patients: evidence of synovitis and extracapsular inflammatory changes by fat suppression magnetic resonance imaging.

Polymyalgia rheumatica (PMR) is an inflammatory condition of unknown etiology characterized by diffuse pain and morning stiffness involving neck, shoulder, and pelvic girdles. To facilitate an understanding of PMR and its proper diagnosis, we evaluated clinical symptoms, laboratory data, and radiographic findings of 32 Japanese patients with it. Distal musculoskeletal manifestations were more frequently observed than had been thought before (81% of the patients), and peripheral arthritis was most common (75%). The joints most often affected were knees and wrists, and most episodes were presented as bilateral oligo- or polyarthritis. A swelling of hands was observed in 34% of the patients. Using contrast-enhanced fat suppression magnetic resonance imaging (MRI) of the shoulder, we found the evidence of subacromial and subdeltoid bursitis (100%), glenohumeral joint synovitis (93%), and biceps tenosynovitis (57%) in the PMR patients examined. Inflammatory changes in soft tissues around the joint capsule were prominent. By knee MRI, suprapatellar bursitis and joint synovitis were visualized in all cases examined, and extracapsular abnormalities were also prominent in 90% of the patients. Serum matrix metalloproteinase-3, a parameter of synovial inflammation, was significantly increased in PMR patients. Anticyclic citrullinated peptide antibody was useful for differential diagnosis between PMR and elderly onset rheumatoid arthritis. In conclusion, joint and periarticular synovitis seems to be commonly and primarily responsible for the proximal and distal musculoskeletal symptoms of PMR. The presence of the extracapsular change, probably a nonspecific extension of synovitis, can explain the severe discomfort that radiates toward the periphery. To avoid making a wrong diagnosis, we should be aware that peripheral synovitis is one of the hallmarks of PMR.

Pneumocystis jiroveci pneumonia in a patient with rheumatoid arthritis as a complication of treatment with infliximab, anti-tumor necrosis factor alpha neutralizing antibody.

We report that a-63-year-old woman developed Pneumocystis jiroveci pneumonia (PCP) as a complication from treatment with infliximab for rheumatoid arthritis. Although there was neither symptoms of dyspnea nor typical observations on a chest X-ray examination, low levels of oxygen saturation and findings of high-resolution chest computed tomographic scanning suggested a possibility of interstitial pneumonia. A polymerase chain reaction-based detection of Pneumocystis jiroveci in induced sputum allowed an early diagnosis of PCP and subsequent effective treatment.

Palladium catalyzed cross-coupling reaction of 5-tributylstannyl-4-fluoropyrazole.

The palladium catalyzed cross-coupling reactions of aryl iodides and 5-tributylstannyl-4-fluoropyrazole prepared from fluoro(tributylstannyl)acetylene proceeded smoothly giving the corresponding 5-aryl-4-fluoropyrazole in good yields.