CASE OF THE MONTH Lung Disease in Rheumatoid Arthritis 61 year old male Maōri Height: 174 cm Weight: 104.6kg BMI: 34.55 Problems 1. Rheumatoid related interstitial lung disease with UIP pattern 2. Secondary traction bronchiectasis 3. Previous pneumonitis 4. Seropositive arthropathy and gout 5. Hypertension Presentation Gentleman is a known patient to the respiratory clinic with Rheumatoid related interstitial lung disease with UIP pattern reporting that he is continuing to struggle with increasing breathlessness and reduced exercise tolerance. He has now found that he can not do as much around the home or his farm or as much when working, such as walking to and from meetings. He continues on prednisone and azathioprine, and control of his arthropathy is currently good. On examination oxygen saturations were 98% breathing air at rest. He had bibasal crackles which again seem to have improved. His lung function is stable. Given his increase in symptoms and reduced exercise tolerance despite stability in the signs of static lung function, a cardiopulmonary exercise test was arranged. Pulmonary Function Tests November 2013 Measured Normal Range (NHANES III Caucasian) FVC (L) 2.89 3.6-5.4 FEV1 (L) 2.24 2.6-4.1 FEV1/FVC (%) 77 65.8-85.1 Normal Range (ERS 1993) TLC (L) 4.42 5.7-8.0 FRCpleth (L) 1.80 2.5-4.5 RV (L) 1.39 1.7-3.1 RV/TLC (%) 31 28.8-46.7 DLco (mmol/kpa.min) 6.00 7.0-11.6 DLco/VA (DLco/L) 1.50 Ref: 1.36 VA (L) 4.04 5.7 8.0 IC (L) 2.68 All tests were acceptable and reproducible within ATS/ERS guidelines The PFT results show a restrictive defect; TLC, FEV1 and FVC < LLN with no spirometric evidence of airflow obstruction. Diffusion shows a reduced DLCO in the presence of reduced VA and normal DL/VA.
Cardiopulmonary Exercise Test Results December 2013 The referral for the cardiopulmonary exercise test was requested to assess the reason for worsening shortness of breath and reduced exercise tolerance. Spirometry (NHANES III) Ref CI Measured %Ref FVC (L) 4.49 0.89 3.00 67 FEV1 (L) 3.39 0.75 2.36 70 FEV1/FVC (%) 75 10 79 IC (L) 2.62 MVV calculated: FEV1 x40 (L) 94.4 CPET (Neder et al.)
UCLA 9 panel plot The cardiopulmonary exercise test was performed on a SensorMedics Vmax metabolic cart using a cycle ergometer. Heart and ECG was measured using a GE CardioSoft 12-lead ECG system. The exercise protocol consisted of 3-minutes sitting on the cycle ergometer with no exercise followed by 3-minutes unloaded exercise (at 10 watts) followed by a 10-watt ramp protocol to exhaustion. (The unloaded 3-minutes is at 10-watts as this is the lowest setting for the cycle ergometer on this system.) Functional Capacity The patient completed progressive exercise for 13-minutes reaching a peak work rate of 133 watts. The maximum oxygen uptake (VO2 peak) was 2.531 L/min, 105% predicted. The VO2 max adjusted for weight was 22.5 ml/kg/min. The anaerobic threshold (AT) occurred at 9.5 ml/kg/min, 44% predicted max (normal >40%) Respiratory/Ventilatory The minute ventilation (VE) at max was 82.6 L/min. The breathing reserve (BR) [MVV-VE/MVV] was -3% (normal >10%). The VD/VT (estimated from PetCO2) at rest was 0.41 (normal 0.3) and at maximum exercise 0.15 (normal <0.20). Gas Exchange The SpO2 was 95% at rest and reached a nadir of 91% at maximum exercise returning to 98% within 5-minutes post exercise.
Cardiovascular The heart rate at peak VO2 was 160bpm, 101% predicted. The oxygen pulse was 14.7 ml/beat, 105% predicted. The blood pressure was 104/80 mmhg at rest and 110/80 mmhg at maximum exercise measured manually with a cuff and sphygmomanometer. ECG showed occasional VPC at rest with increasing number of multifocal VPC at peak and early recovery.. Reason for Test End Leg fatigue RPE 10/10 Question Does the cardiopulmonary exercise test indicate any reason for the shortness of breath on exercise relating to either respiratory or cardiac limitations? Impression The cardiopulmonary exercise test shows ventilation limitation with a breathing reserve of -3 (normal >10). Exercise tolerance was good with a normal response for VO2, VE and heart rate and, an AT at 44% predicted VO2max. SpO2 recording shows mild desaturation at AT with a continuing decline in oxyhaemoglobin desaturation through to the end of exercise. Impression is of a ventilatory limited response to exercise with normal cardiac response and a mild ventilation perfusion mismatch.
Lung Disease in Rheumatoid Arthritis Carlotta Nannini, Jay H. Ryu, Eric L. Matteson. Curr Opin Rheumatol. 2008;20(3):340-346. (full article available at http://www.medscape.com/viewarticle/573647_1) Rheumatoid arthritis (RA) is traditionally considered a disorder in which inflammatory changes predominate the articular and related structures. Clinical observations and studies, however, have also drawn attention to the prevalence of widely disseminated lesions in other regions of the body, thus pointing out the systemic nature of the disease. Indeed, nearly 50% of patients with RA demonstrate some type of extraarticular manifestation including serositis, pneumonitis, myocarditis, valvulitis, renal involvement, myositis, arteritis, peripheral neuritis, involvement of the central nervous system, and hematological changes. The prevalence of RA in the general population ranges from 0.5 to 2%. Women aged 40 years and older are most commonly affected. Survival in patients with RA is significantly lower than that expected in the general population. The strongest predictors of premature mortality appear to be cardiovascular disease and the presence of RA-related complications, specifically, extraarticular manifestations of the disease and associated comorbidities. A variety of pulmonary manifestations (Table ) are associated with RA. Structure Pleura Airway Parenchyma Blood vessel Respiratory muscle Findings Pleural effusion/pleuritis, Pneumothorax Cricoarytenoid arthritis, Bronchiectasis, bronchioloitis (constrictive bronchioloitis, follicular bronchioloitis, diffuse panbronchiolitis) Interstitial pneumonitis (UIP, NSIP, OP, DAD, LIP), necrobiotic nodules, Caplan s syndrome, infections, drug-induced pneumonitis Pulmonary vasculitis, pulmonary hypertension, pulmonary haemorrhage Respiratory muscle/diaphragm weakness DAP: diffuse alveolar damage; LIP: lymphocytic interstitial pneumonia; NSIP: nonspecific interstitial pneumonia; OP: organising pneumonia; UIP: unusual interstitial pneumonia Pulmonary function tests (PFTs) including the capacity of the lung to diffuse carbon monoxide seem to be more sensitive for revealing interstitial lung disease (ILD). The prevalence of restrictive defect in consecutive patients is not high (5 15%), but a reduction in the capacity of the lung to diffuse carbon monoxide is observed in more than 50% of the patients with RA. High-resolution computed tomography (HRCT) is highly sensitive for detecting the presence of ILD and is abnormal in up to 80% of the patients clinically suspected of ILD and RA (range 5 80%). Clinical manifestations associated with ILD are nonspecific and usually include progressive exertional dyspnea and nonproductive cough. In the early stages of ILD, patients may not experience any respiratory symptoms. Forms of Lung Disease in Rheumatoid Arthritis Pleural Disease Pleural involvement is the most common manifestation of lung disease in RA. Although its prevalence has been estimated to be less than 5%, 20% of RA patients have symptoms related to pleural disease, and a high frequency (40 75%) of pleural involvement is noted in autopsy reports. Treatment includes the drainage for recurrent symptomatic effusion, administration of oral corticosteroids, and treatment for the underlying RA. Surgical decortication must be considered if extensive pleural thickening results in restrictive lung disease. Rheumatoid Nodules
Rheumatoid lung nodules are more common in men than in women and are usually asymptomatic. They usually present more of a diagnostic than a therapeutic challenge. Rheumatoid lung nodules are detected on chest radiograph in about 0.2% of unselected patients with RA and more frequently on HRCT (4%). The clinical course of pulmonary nodules is variable. The nodules may precede the clinical manifestation of RA or be concurrent. They may increase in size, resolve spontaneously, or appear at new sites as older nodules resolve. Interstitial Lung Disease Idiopathic interstitial pneumonias are a heterogeneous group of nonneoplastic diseases resulting from damage to the lung parenchyma by varying patterns of inflammation and fibrosis. These disorders affect not only the interstitium (space between endothelial and epithelial basement membranes) but also the adjacent airspaces, the peripheral airways, and the vessels. The main histologic patterns of ILD associated with RA are UIP, nonspecific interstitial pneumonia (NSIP), organizing pneumonia (also called bronchiolitis obliterans organizing pneumonia), and diffuse alveolar damage. These histologic patterns of interstitial pneumonias correlate with different radiological features. HRCT best depicts the underlying radiological pattern. The presence of fibrosis determines the alteration of lung architecture ranging from coarse fibrotic changes (honeycombing fibrosis in UIP) or to relatively preserved architecture with mild-to-moderate interstitial chronic inflammation and fibrosis (NSIP). The most frequent histopathologic pattern found in RA-associated ILD is UIP followed by NSIP and organizing pneumonia combined with inflammatory airways disease. In general, UIP is associated with a significantly worse prognosis and a poor response to corticosteroid treatment. The outcome of patients with fibrotic NSIP, however, may also be poor. Some of this apparent contradiction may be attributed to difficulties in making the histologic distinction between UIP and NSIP in advanced disease. Occurrence of UIP in patients with RA appears to be associated with a better prognosis than to IPF, that is, idiopathic UIP. Airways Involvement Studies in which RA patients and controls are matched for age, sex, and smoking habits reveal indices of airflow to be significantly lower in patients with RA, with a prevalence of pulmonary functional test abnormalities of 38%. In a more recent study, the prevalence of airways obstruction in 81 patients with RA who did not have smoking habit was 16%. This is significantly higher than prevalence in a comparison group of patients with non-ra joint disease who were matched for age and sex. Cricoarytenoid arthritis and bronchiectasis are the major manifestations of large airways involvement. Direct or indirect laryngoscopy and computed tomography scanning reveal cricoarytenoid abnormalities in 75% of patients. Clinical involvement is less frequent. HRCT has demonstrated that bronchiectasis is a common finding in RA, though symptomatic bronchiectasis is unusual. Radiologic findings of bronchiectasis or bronchiolectasis have been described in 30% of patients with RA who are undergoing HRCT. The pulmonary manifestations of RA also include bronchiolar disease such as follicular bronchiolitis and constrictive bronchiolitis (also called bronchiolitis obliterans). These diseases are usually seen in patients with positive rheumatoid factor and active joint disease. The symptoms are characterized by dyspnea and nonproductive cough. Although chest radiograph is generally normal, computed tomography may show areas of air trapping, small nodular opacities in centrilobular distribution (follicular bronchiolitis and bronchiolitis
obliterans), patchy areas of low attenuation (bronchiolitis obliterans), and peribronchial thickening (follicular bronchiolitis and bronchiolitis obliterans). PFTs reveal airflow obstruction. Pulmonary Hypertension Isolated pulmonary hypertension with clinical manifestations is rare in patients with RA. The incidence of pulmonary artery systolic pressure higher than 30 mmhg suggests that pulmonary hypertension is significantly higher in patients with RA (26.7 versus 4.5% in controls; P = 0.03). Using Doppler echocardiography, pulmonary hypertension was found to be secondary to lung disease in 6% of an unselected population of patients with RA. Drug-induced Lung Disease Several of the medications used to treat RA can be associated with lung injury. The incidence of pulmonary toxicity in patients treated with methotrexate for RA is 1 5%. There appears to be no relationship between the occurrence of pulmonary toxicity and cumulative dosage. Toxicity is rare with doses less than 20 mg per week, although more recent studies have reported that methotrexate pneumonitis occurs with a dose of 5 mg per week. Interstitial pneumonia as an adverse reaction of leflunomide is rare. The incidence of such cases is reported to be 0.02% in Western countries. In Japan in 2003, 16 cases (0.48%) of ILD, including five fatal cases (0.15%), were associated with leflunomide therapy among 3360 registered patients. In recent years, a number of cases have been observed linking the use of the tumor necrosis factor-α (TNF-α) inhibitors, infliximab, etanercept, and adalimumab, to ILD. The precise pathogenetic mechanism involved in the development or worsening of pulmonary fibrosis after TNF blockade remains elusive. Kuroki et al. have demonstrated that TNF-α plays an important role in limiting pulmonary inflammation in mouse model of bleomycin-induced pneumopathy. Conclusion A variety of pulmonary manifestations are associated with RA (pleurisy, parenchymal nodules, interstitial involvement, airways diseases) that influences morbidity and increases the risk of mortality. Recent advances in HRCT reveal basilar ground-glass and reticulonodular opacities, which along with supporting clinical and physiologic data in asymptomatic patients with RA now suggest the earlier diagnosis. The majority of patients with progressive pulmonary symptoms, when treated with corticosteroids have equivocal results. Only few case reports document the efficacy of immunosuppressive or cytotoxic medications.