The effect of anti-tuberculosis treatment on levels of anti-phospholipid and anti-neutrophil cytoplasmatic antibodies in patients with active tuberculosis.

The aim of this study is to determine the prevalence and effect of anti-tuberculosis treatment on anti-phospholipid antibodies and anti-neutrophil cytoplasmatic antibodies (ANCA) in patients with active mycobacterial infections. Thirty-three consecutive patients (age 56 years, 26 males) with recently diagnosed active tuberculosis (TB) were enrolled. Data included clinical disease features, symptom duration, multidrug resistance and presence of HIV. Serum samples taken before and after TB treatment were frozen at -20 °C and tested for anti-cardiolipin IgG (aCL), anti-ß2 glycoprotein IgG (anti-ß2GPI), anti-prothrombin, anti-proteinase 3 (PR3), myeloperoxidase (MPO), bactericidal/permeability (BPI) and lactoferrin. Thirty percent of patients had higher than cut-off value for anti-ß2GPI, and 9 % had increased aCL. The levels of antibodies against ß2GPI and aCL normalized post-treatment. A substantial proportion of patients had high baseline anti-PR3, MPO, BPI and lactoferrin levels. Most anti-lactoferrin and anti-MPO levels decreased post-treatment, while anti-PR3 increased in most of the baseline-positive patients. Some patients had de novo anti-PR3 and MPO formation after 6-month treatment. Patients with active TB have significantly increased anti-ß2GPI and ANCA titers. While anti-ß2GPI titers normalize post-treatment, ANCA behave in a complex way. Anti-TB treatment may induce normalization of anti-lactoferrin and anti-MPO, and de novo anti-PR3 and MPO formation.

The role of interferon-gamma release assays in the diagnosis of active tuberculosis.

BACKGROUND: Interferon-gamma release tests are appealing alternatives to the tuberculin skin test (TST) for latent tuberculosis infection. OBJECTIVES: To determine the yield of the Quantiferon TB Gold test (QFT-G) in the diagnosis of active tuberculosis disease, with a focus on elderly patients, human immunodeficiency virus (HIV) co-infection, and extra-pulmonary tuberculosis (EPTB). METHODS: The QFT-G test was performed in 98 patients suspected of having active tuberculosis. The results were evaluated for each subgroup of patients and compared to the results of the TST. RESULTS: Active tuberculosis was diagnosed in 92 of the 98 patients. Sixteen (17.3%) were elderly patients (over age 70), 15 (16%) were co-infected with HIV, and 14 (15%) had EPTB. QFT-G was positive in 49 patients (53%) and indeterminate in 4. The results were not significantly affected by HIV coinfection (P = 0.17), old age (P = 0.4), orthe presence of EPTB (P = 0.4). There was a good correlation between the TST and the QFT-G test (P < 0.001). In EPTB and in the elderly, the QFT-G test appears to be better than the TST. CONCLUSIONS: The QFT-G test is suboptimal in its ability to detect active tuberculosis and should not be used to exclude it.

Pulmonary resection for multidrug-resistant tuberculosis: the Israeli experience (1998-2011).

BACKGROUND: Multidrug-resistant tuberculosis (MDR-1B) presents a difficult therapeutic problem due to the failure of medical treatment. Pulmonary resection is an important adjunctive therapy for selected patients with MDR-TB. OBJECTIVES: To assess the efficacy of pulmonary resection in the management of MDR-TB patients. METHODS: We retrospectively reviewed the charts of MDR-TB patients referred for major pulmonary resections as part of a treatment strategy. The operations were performed in the departments of thoracic surgery at Assaf Harofeh and Wolfson Medical Centers. For the period under study, 13 years (1998-2011), we analyzed patients' medical history, bacteriological, medical and surgical data, morbidity, mortality, and short-term and long-term outcome. RESULTS: We identified 19 pulmonary resections (8 pneumonectomies, 4 lobectomies, 1 segmentectomy, 6 wedge resections) from among 17 patients, mostly men, with a mean age of 32.9 years (range 18-61 years). Postoperative complications developed in six patients (35.3%) (broncho-pleural fistula in one, empyema in two, prolonged air leakin two, and acute renal failure in one). Only one patient (5.84%) died during the early postoperative period, three (17.6%) inthe late postoperative period, and one within 2 years after the resection. Of 12 survivors, 9 were cured, 2 are still under medical treatment, and 1 is lost from follow-up because of poor compliance. CONCLUSIONS: Pulmonary resection for MDR-TB patients is an effective adjunctive treatment with acceptable morbidity and mortality.

Human antibodies targeting a Mycobacterium transporter protein mediate protection against tuberculosis.

Mycobacterium tuberculosis (Mtb) exposure drives antibody responses, but whether patients with active tuberculosis elicit protective antibodies, and against which antigens, is still unclear. Here we generate monoclonal antibodies from memory B cells of one patient to investigate the B cell responses during active infection. The antibodies, members of four distinct B cell clones, are directed against the Mtb phosphate transporter subunit PstS1. Antibodies p4-36 and p4-163 reduce Mycobacterium bovis-BCG and Mtb levels in an ex vivo human whole blood growth inhibition assay in an FcR-dependent manner; meanwhile, germline versions of p4-36 and p4-163 do not bind Mtb. Crystal structures of p4-36 and p4-170, complexed to PstS1, are determined at 2.1 Å and 2.4 Å resolution, respectively, to reveal two distinctive PstS1 epitopes. Lastly, a prophylactic p4-36 and p4-163 treatment in Mtb-infected Balb/c mice reduces bacterial lung burden by 50%. Our study shows that inhibitory anti-PstS1 B cell responses arise during active tuberculosis.

Active tuberculosis and human immunodeficiency virus co-infection in Israel: a retrospective study.

BACKGROUND: Tuberculosis is the most common opportunistic infection among people infected with human immunodeficiency virus and its first cause of morbidity and mortality. OBJECTIVES: To analyze the characteristics of a population in Israel with both tuberculosis disease and HIV infection in order to identify factors that contribute to outcome. METHODS: The study group comprised patients hospitalized in the Pulmonary and Tuberculosis Department of Shmuel Harofeh Hospital during the period January 2000 to December 2006. They were located by a computer search of the hospital registry and the pertinent data were collected. RESULTS: During the study period 1059 cases of active tuberculosis disease were hospitalized; 93 of them were co-infected with HIV. Most of them came from endemic countries (61.2% from Ethiopia and 20.4% from the former Soviet Union; none of them was born in Israel). Ten percent of the cases were multiple-drug resistant and 32% showed extrapulmonary involvement. The response rate to the treatment was good, and the median hospitalization time was 70 days. The mortality rate was 3.2%. CONCLUSIONS: Despite the high prevalence of pulmonary disease in our group, the short-term outcome was good and the Mycobacterium was highly sensitive to first-line drugs. These encouraging results can be attributed to the fact that tuberculosis patients in Israel are identified early and treated continuously and strictly, with early initiation of antiretroviral therapy, which together ensure that the development of drug resistance is low.

Combination therapy with prostacyclin and tadalafil for severe pulmonary arterial hypertension: a pilot study.

Despite the introduction of new drugs that have changed the course of pulmonary arterial hypertension (PAH), some patients are still refractory to treatment and deteriorate rapidly. Long-acting phosphodiesterase-5 inhibitors are a new class of drugs that are effective in PAH. This prospective study assessed the potential of combination therapy with prostacyclin and tadalafil for treatment of severe PAH. We report four cases of severe PAH that deteriorated despite prostacyclin therapy. Two patients had Eisenmenger syndrome, one had pulmonary hypertension associated with scleroderma and one had histiocytosis X. All were treated with tadalafil, 10-20 mg once daily, in addition to prostacyclin. After 3 months of treatment, all patients improved clinically, with an increase in mean 6MWD from 214 to 272 m. In three patients, the New York Heart Association functional class decreased from IV to III. Echocardiograms showed no significant changes in pulmonary arterial pressure. Although this study was limited by the small sample size, it suggests that tadalafil in combination with prostacyclin is an effective treatment for severe PAH. Tadalafil may be beneficial for the treatment of patients with advanced disease.

[Azithromycin as a novel treatment for bronchiolitis obliterans syndrome].

Bronchiolitis obliterans syndrome (BOS) is one of the main causes of mortality after lung and bone marrow transplantation. Up to 75% of lung transplantation patients develop BOS within 5 years, whereas after bone marrow transplantation 14% of the patients develop the disease with 65% mortality within 3 years. Patients demonstrate gradual decrease in pulmonary functions with no significant anatomic/imagine findings. Therapeutic trials with high dose systemic corticosteroids, immune suppression and immunomodulation did not show any significant success. However, macrolides and especially azithromycin have recently been reported as highly efficient for BOS. This review summarizes information on the disease focusing on the clinical experience with azithromycin as a treatment for BOS.

Development of malignancy following lung transplantation.

BACKGROUND: A substantial excess risk of certain malignancies has been demonstrated after organ transplantation. Immunosuppressive treatment to prevent allograft rejection is probably the main cause. METHODS: We reviewed retrospectively all medical records of the 121 patients that underwent lung and heart-lung transplantation from 1992 until December 2004. We compared our results to the International Society for Heart and Lung Transplantation (ISHLT) registry data and previous reports concerning lung transplantation. RESULTS: 102 of the 121 patients survived for 3 months to 12 years. Malignancies developed in 16 patients, as follows: lymphoproliferative disorder in 3, Kaposi's sarcoma in 3, other nonmelanoma skin cancers in 7, urinary bladder transitional cel carcinoma in 3, and colon cancer in 1. Patients with malignancy were older at transplantation than those without (mean +/- SD, 54.1+/-7.8 vs. 49.5+/-14.2 years; P=0.03). Fourteen had smoked in the past. Four died of bronchiolitis obliterans. In comparison with the ISHLT, we observed more skin cancer and transitional cell carcinoma (12.8% vs. 0.7% and 3.8% vs. 0.03%, respectively) and a similar frequency of posttransplant lymphoproliferative disease. CONCLUSIONS: We conclude that malignancy is a common complication after lung transplantation. In Israel, which is sunny most of the year, skin cancers and transitional cell carcinoma of bladder are more common. Modification of the immunosuppression late posttransplantation may reduce the risk of cancer. Patients should also be counseled to avoid sun exposure and ensure adequate hydration.

Right upper lobe 'window' in right main bronchus stenting.

Stent insertion for bronchial stenosis has become common practice in lung transplantation and advanced lung malignancy, and for external compression of the airways for other reasons. Right main bronchus stenting may require blocking the right upper lobe by the stent, placing the patient at risk of recurrent pneumonia and atelectasis. In this study, three patients after insertion of a metal stent to the right main bronchus are described. In all cases, the right upper lobe was covered by the stent, and a laser (Nd:YAG) procedure was used to open a 'window' in the stent toward the right upper lobe with a follow-up of 1 year. We conclude that stent insertion to the right main bronchus may be followed by a laser therapy to open a 'window' toward the right upper lobe.

Pulmonary arterial hypertension associated with autoimmune disease: a single medical center experience.

BACKGROUND: New drugs have significantly improved the prognosis and quality of life of patients with pulmonary arterial hypertension. However, PAH associated with autoimmune disease, particularly progressive sclerosis, remains a very serious problem. OBJECTIVES: To evaluate whether the course of the disease and survival is significantly different in patients with PAH related to autoimmune disease as compared to other patients with PAH and to determine the prognostic factors in these patients. METHODS: We retrospectively compared 24 patients with PAH associated with autoimmune disease to 42 patients with other causes of PAH. We focused on the clinical and hemodynamic parameters and on the outcome. RESULTS: The early mortality rate was slightly higher in patients with PAH associated with autoimmune disease (13% after the first year, 25% after the fifth year). The prognostic factor was a shorter distance on the 6 minute walking distance test (r = 0.2, P= 0.01). CONCLUSIONS: The early detection of PAH associated with autoimmune disease should encourage earlier and more aggressive treatment than in idiopathic PAH.

Accuracy of virtual bronchoscopy for grading tracheobronchial stenosis: correlation with pulmonary function test and fiberoptic bronchoscopy.

STUDY OBJECTIVES: To compare the accuracy of virtual bronchoscopy (VB) with fiberoptic bronchoscopy (FOB) and pulmonary function testing (PFT) for the assessment of tracheal stenosis and bronchial anastomotic stenosis. DESIGN: Prospective case series. SETTING: Pulmonary institute of major tertiary university-affiliated center. PATIENTS: The study group included 10 lung transplant recipients and 13 patients with central airway stenosis. INTERVENTIONS: All patients underwent PFT, VB, and FOB. All cases were graded by each modality on a scale of 1 to 3, and the findings were compared between modalities. RESULTS: Mean +/- SD stenosis score was 2.0 +/- 0.79 for PFT, 1.62 +/- 0.73 for FOB, and 1.82 +/- 0.77 for VB. A statistically significant correlation was found between VB and FOB scores (p < 0.0001, r = 0.76) and between VB scores and PFT (p = 0.03, r = 0.45). There was no correlation between PFT and FOB. CONCLUSIONS: VB grading of tracheobronchial stenosis is well correlated with PFT. VB may be used to evaluate patients with known tracheobronchial stenosis after treatment and thereby reduce the frequency of repeated invasive FOB performed for that purpose. The correlation of VB with PFT may improve the reliability of this approach.

Pregnancy outcome in patients with pulmonary arterial hypertension receiving prostacyclin therapy.

BACKGROUND: Pregnancy is contraindicated in cases of pulmonary hypertension, a highly morbid disease affecting young women of childbearing age. CASES: We describe the pregnancies of 3 patients with pulmonary arterial hypertension (idiopathic, Eisenmenger syndrome, and related to systemic lupus erythematosus). They received epoprostenol and low-molecular-weight heparin throughout pregnancy. The patient with Eisenmenger syndrome started epoprostenol in gestational week 16. Cesarean delivery under general anesthesia was performed at 28-33 weeks of gestation; early delivery was necessary in the patient with Eisenmenger syndrome because of fetal growth restriction. All deliveries were uneventful, and birth weights were 1,700, 1,500, and 795 g. There were no postpartum complications. CONCLUSION: Pregnancy in women with pulmonary hypertension should still be considered high risk for both mother and child, but stable patients on epoprostenol may successfully complete pregnancy.

Concomitant upper-lobe bullous emphysema, lower-lobe interstitial fibrosis and pulmonary hypertension in heavy smokers: report of eight cases and review of the literature.

INTRODUCTION: Smoking can cause a variety of pulmonary interstitial diseases. Pulmonary fibrosis has traditionally been considered a non-smoking-related disease. Recently, however, evidence of smoking-induced fibrosis has emerged. SUBJECTS AND METHODS: A group of eight patients from the pulmonary clinic in Rabin Medical Center with a combine presentation of fibrosis and emphysema was identified retrospectively. All patients underwent chest computed tomography and pulmonary function tests. One patient underwent lung-heart transplantation and a complete review of his lung pathology was obtained. Transbronchial biopsy was performed in 3 additional patients and echocardiography was performed to evaluate the pulmonary vasculature. RESULTS: Upper-lobe emphysema with bulluos changes was found in all patients. In addition, a basal interstitial process was recognized, ranging from ground glass opacities to severe pulmonary fibrosis, with honeycombing. The radiological findings matched the pathological results of combined emphysema and usual interstitial pneumonia. Pulmonary function tests were also in accord, showing severe hypoxemia with mild obstruction, normal-to-mildly reduced lung volumes and a severe decrease in diffusion capacity. Most of the patients had moderate-to-severe pulmonary hypertension as well as diffuse coronary artery disease. CONCLUSION: Our findings are in line with emerging evidence that the spectrum of interstitial damage caused by smoke includes not only Langerhans cell hystiocytosis, respiratory bronchiolitis or desquamative interstitial pneumonia but also advanced usual interstitial pneumonitis as well. We believe that in some patients smoking plays a destructive role by a variety of mechanisms and can cause emphysema, lung fibrosis as well as pulmonary vasculopathy and hypertension. Future studies are needed to define the genetics and pathophysiology of this uncommonly reported clinical syndrome.

Successful steroid withdrawal in lung transplant recipients: result of a pilot study.

OBJECTIVE: Corticosteroids play a key role in immunosuppression after transplantation. However, because chronic steroid treatment may cause significant morbidity and mortality, steroid-free immunosuppression remains a desirable goal. To the best of our knowledge, there are no reports on successful steroid withdrawal (SW) in lung transplant recipients. METHODS: The study group included 35 patients who underwent heart-lung, double-lung or single-lung transplantation. Criteria for initiation of SW were stable pulmonary function tests and absence of clinical or bronchoscopic evidence of acute or chronic rejection in the last 6 months. Pulmonary function, blood pressure and metabolic parameters were compared between the patients who underwent SW and those who did not. RESULTS: Eight patients (23%) underwent SW. Median follow-up was 19 months (range 11-23 months). Compared to the non-withdrawal group, the withdrawal group was older (60+/-6 vs. 52+/-13 years, P=0.01, r=0.49), had higher rates of emphysema (88% vs. 18%, P=0.01) and use of a cyclosporine-based regimen (62% vs. 26%, P=0.0001), and had longer time from transplantation to the withdrawal attempt (70+/-13 vs. 29+/-26 months, P=0.0002). The SW group showed no adverse effects in graft function and no deterioration on pulmonary function tests. SW had a beneficial metabolic effect, with a decrease in mean cholesterol level from 229+/-45 to 194+/-25 mg/dl (P=0.02) and no significant change in weight, systolic blood pressure or glucose level. In the non-withdrawal group, mean cholesterol levels increased from 175+/-34 to 209+/-57 mg/dl (P=0.0005), weight increased from 72+/-15 to 80+/-14 kg (P=0.0001), and systolic blood pressure increased from 125+/-15 to 139+/-16 mmHg (P=0.001); glucose levels did not change. There was a significant correlation between total cholesterol level and weight in both groups (P=0.0006, r=-0.56 and P=0.01, r=-0.46, respectively). CONCLUSIONS: Late SW is safe in stable patients after lung transplantation. There was no evidence of rejection or a deterioration in pulmonary function. Lipid profile improvement and blood pressure stabilization accompanied the termination of steroid therapy.

[Pulmonary hypertension--classification and treatment: new guidelines].

Pulmonary arterial hypertension is a severe pulmonary vascular disease characterized by elevated pulmonary vascular resistance and low cardiac output. Prior to prostacyclin therapy, it was a fatal disease with a median survival of 3 years. In recent years, the understanding and treatment of the disease have significantly improved patient outcome. The new therapeutic guidelines are based on the finding that vasoconstriction and vascular remodeling correlated with endothelial dysfunction, endothelin overexpression and diminished prostacyclin and nitric oxide synthesis. This article outlines the new classification and the current therapeutic guidelines accepted in the world presenting the role of prostacyclins, endothelin antagonist, phosphodiesterase V inhibitor, and the potential value of combination therapies.

Significance of a plasma D-dimer test in patients with primary pulmonary hypertension.

BACKGROUND: D-dimer, a degradation product of fibrin, has been increasingly used as a marker or prognostic factor in various thrombotic diseases. OBJECTIVE: To assess the significance of a d-dimer test in patients with primary pulmonary hypertension (PPH). PATIENTS AND METHODS: Fourteen patients with PPH (12 women and 2 men) aged 25 to 68 years (mean +/- SD age, 50 +/- 14 years) entered the study. Plasma d-dimer was determined by Miniquant assay (Biopool International; Venture, CA) 3 +/- 5 months after the disease onset, and patients were followed up for 1 year. We compared the d-dimer levels to the demographic, clinical, and hemodynamic data of the patients. RESULTS: D-dimer levels were positively correlated with New York Heart Association classification (r = 0.59, p = 0.01) and pulmonary artery pressure (r = 0.43, p = 0.03) and were negatively correlated with oxygen saturation (r = - 0.45, p = 0.03) and 6-min walk distance (r = - 0.49, p = 0.04). One-year survival was also negatively correlated with d-dimer (point-biserial r = - 0.71, p = 0.004), with a higher d-dimer value associated with poorer survival. No significant correlations were found between d-dimer values and sex, age, diffusing capacity of the lung for carbon monoxide, or cardiac index. CONCLUSION: D-dimer levels may have a role in the evaluation of patients with PPH. This simple, noninvasive test may be helpful for identifying patients who are at a higher risk for severe disease.

Unexplained severe pulmonary hypertension in the elderly: report on 14 patients.

BACKGROUND: Unexplained pulmonary hypertension is assumed to occur mainly in young adults. OBJECTIVE: To describe the features of the disease in older patients and compare them to those in PHT patients of all ages. METHODS: We conducted a retrospective evaluation of the files of patients over 65 years of age in whom UPHT was diagnosed between 1987 and 1999 at two PHT centers serving a population of 4 million. Patients were followed for survival until March 2003. Clinical variables of the study patients were compared with those in PHT patients of all ages. RESULTS: The study group included 14 patients, 10 females and four males, with a mean age of 70.5 +/- 6.7 years. The calculated mean annual incidence of UPHT for the study population was one new case per year per million persons. Seven patients (50%) had systemic hypertension. The mean interval from onset of symptoms to diagnosis was 8.3 months. At diagnosis, 64% of patients had functional capacity of III-IV according to the New York Heart Association classification, and 43% had right heart failure. Mean systolic pulmonary artery pressure was 80 +/- 21 mmHg, peripheral vascular resistance 11.7 +/- 7 mmHg/L/min, cardiac index 2.16 +/- 0.81, and mean right atrial pressure 10.5 +/- 5.9 mmHg. Median survival time was 43 months; survival rates for 1 year, 3 years and 5 years were 92.6%, 50% and 40%, respectively. Compared to data from the U.S. National Institute of Health Registry, UPHT in older patients is more common in females, but the incidence as well as clinical, hemodynamic and survival parameters are similar to those in PHT patients at any age. CONCLUSIONS: UPHT occurs in the elderly more frequently than previously thought, with similar features in PHT patients of all ages. The coexistence of systemic and pulmonary hypertension warrants further investigation.

Continuous intravenous epoprostenol in pulmonary hypertension: the Israel experience.

BACKGROUND: Primary idiopathic pulmonary hypertension is a rapidly progressive disease with a median survival of less than 3 years. Recently its prognosis was shown to dramatically improve with the use of epoprostenol, an arachidonic acid metabolite produced by the vascular endothelium, which increases the cardiac output and decreases the pulmonary vascular resistance and pulmonary arterial pressure. This drug enhances the quality of life, increases survival and delays or eliminates the need for transplantation. OBJECTIVE: To review the experience of Israel hospitals with the use of epoprostenol. METHODS: The study group comprised 13 patients, 5 men and 8 women, with an age range of 3-53 years. All patients suffered from arterial pulmonary hypertension. Epoprostenol was administered through a central line in an increased dose during the first 3 months, after which the dose was adjusted according to the clinical syndrome and the hemodynamic parameters. RESULTS: After 3 months the mean dose was 10 ng/kg/min and the pulmonary artery pressure decreased from 7 to 38%. After one year, the PAP decreased at a slower rate. Two cases required transplantation, three patients died, and seven continued taking the drug (one of whom discontinued). Four episodes of septicemia were observed. Today 10 patients are alive and well and 7 continue to take epoprostenol. CONCLUSION: We found that epoprostenol improves survival, quality of life and hemodynamic parameters, with minimum side effects.

The anti-cyclic citrullinated peptide response in tuberculosis patients is not citrulline-dependent and sensitive to treatment.

INTRODUCTION: Patients with tuberculosis (TB) frequently produce anti-citrullinated protein antibodies (ACPA). The objective of this study is to characterize the citrulline-dependence of the ACPA reactivity in sera of patients with mycobacterium infections. METHODS: Serum samples of 134 patients with untreated mycobacterium infections (122 TB, 12 nontuberculous mycobacterium) were tested for antibodies against both the citrullinated (Cit) and the non-citrullinated (Arg) form of 2 cyclic synthetic peptides. In 33 patients, a follow-up sample was tested six months after starting anti-mycobacterial drugs. RESULTS: A substantial proportion of patients with mycobacterial infections demonstrated antibodies against 0401Cit, 0401Arg, 0722Cit and 0722Arg. Fourteen patients demonstrated anti-0401Cit, 83 anti-0401Arg, 22 anti-0722Cit and 61 anti-0722Arg, while none of these antibodies were detected in the 20 healthy controls. All the patients but one, who were anti-0401Cit and anti-0722Cit positive, demonstrated reactivity against the respective Arg peptide. In the subset of 33 patients with a follow-up test six months after starting treatment, the mean levels of antibodies to 0401Cit, 0401Arg, 0722Cit and 0722Arg significantly decreased after treatment. All the patients who were anti-0401Cit and anti-0722Cit positive turned negative after treatment. The presence of anti-0401Cit/Arg and anti-0722Cit/Arg was found to be significantly correlated with the presence of HIV. CONCLUSIONS: ACPA may be found in patients with TB. In most of the cases, the reactivity is citrulline independent. A positive cyclic citrullinated peptide (CCP) test in these patients should therefore be interpreted with care, and preferably followed by a control ELISA with a non-citrullinated antigen.