Melike Melikoglu

Pulmonary Artery Involvement and Associated Lung Disease in Behçet Disease: A Series of 47 Patients

AbstractPulmonary artery aneurysms (PAAs) are well known causes of mortality and morbidity in Behçet disease (BD). However, pulmonary artery involvement in BD is not limited to PAA; the other main type of pulmonary artery involvement is pulmonary artery thrombus (PAT), with or without associated PAA. In addition, other types of lung disease like nodules and cavities in the lung parenchyma are frequently associated with pulmonary artery involvement, and can be misinterpreted as being due to infection. We surveyed the clinical, radiologic, and laboratory characteristics and outcome of 47 BD patients with pulmonary artery involvement and the associated findings, all seen and followed at a single dedicated tertiary care center.We identified 47 (41 male, 6 female) patients in whom pulmonary artery involvement was diagnosed, who were registered in the multidisciplinary clinic at Cerrahpasa Medical Faculty between January 2000 and December 2007. Mean age at diagnosis was 29 ± 8 years, and mean disease duration to the onset of pulmonary artery involvement was 3.6 ± 4.8 years. Hemoptysis was the most common presenting symptom (79%) followed by cough, fever, dyspnea, and pleuritic chest pain. Thirty-four of 47 patients (72%) presented with PAA, including 8 with associated PAT. The remaining 13 patients (28%) had isolated PAT. Patients with isolated PAT in general have clinical features similar to patients with PAA. However, hemoptysis was less frequent and voluminous in patients with isolated PAT. Most (91%) of the patients had active disease outside the lungs when they presented with pulmonary artery involvement.Forty (85%) patients had nodules and 6 (13%) had cavities when first seen. Peripheral venous thrombosis was present in 36 of 47 (77%) patients, and intracardiac thrombi in 12 of the 36 (33%) patients. Nodules, cavities, and intracardiac thrombi were mainly present in the acute stages of pulmonary artery involvement.Pulmonary artery involvement is usually multiple, and involves mostly descending branches of the pulmonary artery. Pulmonary artery involvement may disappear, but arterial stenosis or occlusions usually develop at the same location. After a mean follow-up of 7 years, 12 of 47 (26%) patients were dead; patients with larger aneurysms were more likely to die. Sixteen of 47 (34%) patients were symptom free, and the remaining 40% had mild dyspnea (13/47) and/or small bouts of hemoptysis (8/47).Pulmonary artery pressure may be elevated, and may indicate a poor prognosis. Mediastinal lymphadenopathy and mild pleural and pericardial effusions may also be observed. Corticosteroids and immunosuppressive agents are the mainstays of treatment; however, refractory cases may require embolization, lobectomy, cavitectomy, and decortication.

Apremilast for Behçet’s Syndrome — A Phase 2, Placebo-Controlled Study

BACKGROUND Oral ulcers, the hallmark of Behçets syndrome, can be resistant to conventional treatment; therefore, alternative agents are needed. Apremilast is an oral phosphodiesterase-4 inhibitor that modulates several inflammatory pathways. METHODS We conducted a phase 2, multicenter, placebo-controlled study in which 111 patients with Behçets syndrome who had two or more oral ulcers were randomly assigned to receive 30 mg of apremilast twice daily or placebo for 12 weeks. This regimen was followed by a 12-week extension phase in which the placebo group was switched to apremilast and a 28-day post-treatment observational follow-up phase. The patients and clinicians were unaware of the study assignments throughout the trial. The primary end point was the number of oral ulcers at week 12. Secondary outcomes included pain from these ulcers (measured on a 100-mm visual-analogue scale, with higher scores indicating worse pain), the number of genital ulcers, overall disease activity, and quality of life. RESULTS The mean (±SD) number of oral ulcers per patient at week 12 was significantly lower in the apremilast group than in the placebo group (0.5±1.0 vs. 2.1±2.6) (P<0.001). The mean decline in pain from oral ulcers from baseline to week 12 was greater with apremilast than with placebo (-44.7±24.3 mm vs. -16.0±32.5 mm) (P<0.001). Nausea, vomiting, and diarrhea were more common in the apremilast group (with 22, 9, and 12 incidents, respectively, among 55 patients) than in the placebo group (with 10, 1, and 2 incidents, respectively, among 56 patients), findings that were similar to those in previous studies of apremilast. There were two serious adverse events in patients receiving apremilast. CONCLUSIONS Apremilast was effective in treating oral ulcers, which are the cardinal manifestation of Behçets syndrome. This preliminary study was neither large enough nor long enough to assess long-term efficacy, the effect on other manifestations of Behçets syndrome, or the risk of uncommon serious adverse events. (Funded by Celgene; ClinicalTrials.gov number, NCT00866359.).

Vascular involvement in Behçet’s syndrome: a retrospective analysis of associations and the time course

OBJECTIVE Some features of Behçets syndrome (BS) tend to go together. We aimed to explore the association and timing of various vascular events in both the venous and the arterial vascular tree. METHODS We conducted a chart survey on the type and time of vascular involvement of BS. The cross-relationships of involvement were assessed by phi correlation coefficients. Multiple correspondence analysis was used to identify patterns of vascular involvement. The risk of vascular recurrence was also estimated. RESULTS We identified 882 patients with vascular involvement among 5970 BS patients (14.7%). Deep vein thrombosis (DVT), almost always in the legs, was the most frequent single vascular event (592/882; 67.1%). The cumulative risk of a recurrent vascular event was 38.4% at 5 years. Patients with extrapulmonary artery involvement (EPAI) were significantly older than those with venous and pulmonary artery involvement (PAI). There were significant correlations between dural sinus thrombosis (DST) and PAI, Budd-Chiari syndrome (BCS) and inferior vena cava syndrome (IVCS) and between IVCS and superior vena cava syndrome (SVCS). Multiple correspondence analysis further indicated clustering of PAI, DST, BCS, IVCS and SVCS. However, EPAI and DVT clustered separately from forms of vascular disease, the separate clustering of the DVT being attributed to its propensity to occur solo. CONCLUSION The most common type of vascular involvement in BS is solo DVT, almost always occurring in the legs. Various forms of venous disease in BS segregate together and PAI is included in this group. EPAI segregates separately.

Atherosclerosis in Behçet's Syndrome

OBJECTIVES We had the impression and preliminary evidence that atherosclerosis was not much increased in Behçets syndrome (BS). Thus, we evaluated the presence of subclinical atherosclerosis in a sizeable group of patients with BS both with major organ involvement and mucocutaneous disease along with diseased and healthy controls. METHODS We studied 239 (162 M/ 77 F; mean age: 40.7+/-7.0) patients with BS. Seventy-two (32 M/ 40 F) had only mucocutaneous and/or joint disease and 167 (130 M/ 37 F) had major organ involvement. Also 100 (24 M/ 76 F; mean age: 44.7+/-7.1) patients with rheumatoid arthritis (RA), 74 (58 M/ 16 F; mean age: 39.4+/-7.0) patients with ankylosing spondylitis (AS) and 156 (83 M/ 73 F; mean age: 39.2+/-6.6) healthy controls (HC) were studied as the control groups. We used B-mode USG to assess the frequency of plaques and intima-media thickness (IMT) in the carotid and femoral arteries. Traditional atherosclerotic risk factors were also evaluated. Men and women were analyzed separately. RESULTS The frequency of plaques and the mean IMT in the carotid and femoral arteries were similar between patients with BS, AS and HC and also between the 2 subgroups of BS, among both men and women. Only men with RA were found to have significantly increased frequency of carotid artery plaques after adjustment for atherosclerotic risk factors. CONCLUSION Increased atherosclerosis is not a prominent feature of BS, even among those patients with major organ involvement.

The Unique Features of Vasculitis in Behçet’s Syndrome

The presence of a true vasculitis is difficult to discern in some of the more common manifestations of Behçet’s syndrome, like the papulopustular lesions of the skin. On the other hand, a true vasculitis is seen in all vessel sizes in the majority of the patients. The pathogenesis is not yet known. A Th1-type inflammatory reaction is seen like in some other primary vasculitides. However, in contrast to other vasculitides, granuloma formation is absent. Behçet’s syndrome is unique among the vasculitides with its differing geographic distribution in disease expression, the distinctly more severe disease among the male, the predominance of venous disease, and the generally abating disease course with lack of associated increased atherosclerosis.

Characterization of the Divergent Wound-Healing Responses Occurring in the Pathergy Reaction and Normal Healthy Volunteers

Behçet’s disease (BD) is a multisystem inflammatory disorder of unknown etiology characterized by recurrent oral and genital ulcerations and uveitis, with varying other manifestations associated with vascular inflammation. A unifying feature of BD inflammation is the skin pathergy reaction (SPR), a nonspecific tissue hyperreactivity to minor trauma involving epithelial disruption. This study compared skin responses to needle prick in BD patients and normal healthy volunteers. Two study groups, each consisting of 10 BD patients with SPR+ and 6 controls, were evaluated using either immunohistochemistry or quantitative real-time PCR to measure inflammatory cell and cytokine levels in biopsy specimens obtained serially from independent sites at 0, 8, and 48 h after needle prick. We found similar cellular infiltration patterns in response to needle prick in BD patients and controls between 0 and 8 h. Further development of this immune response was limited in skin of normal control subjects, with stable or decreased inflammatory mediators observed at 48 h. In contrast, in BD-derived skin specimens, increased influxes of mature dendritic cells, monocytes, and lymphocytes, including T regulatory cells, were noted by 48 h. Similarly, increases in cytokines (IFN-γ, IL-12 p40, IL-15), chemokines (MIP3-α, IP-10, Mig, and iTac), and adhesion molecules (ICAM-1, VCAM-1) were noted at 48 h in the skin of BD patients with SPR+ but not in the skin of normal controls. These results suggest that, in contrast to the self-limited inflammation associated with epithelial disruption of normal skin, BD patients experience marked cellular influxes into the injury site, leading to an exaggerated lymphoid Th1-type response.

Intestinal permeability in Behçet's syndrome

OBJECTIVE To measure the intestinal permeability in patients with Behçets syndrome (BS) and to compare the results with those obtained from healthy and diseased controls. METHOD The study group comprised 34 patients with BS without known gastrointestinal disease. Ten patients with ankylosing spondylitis (AS), 6 with inflammatory bowel diseases (IBD), 17 with systemic lupus erythematosus (SLE), and 15 healthy subjects (HC) constituted the controls. All patients received 100 μCi (3.7 MBq) of chromium-51 EDTA (51Cr-EDTA) as a radioactive tracer after a 72 hour abstinence from all drugs. The percentage of the isotope excreted in a 24 hour urinary specimen was the measure of permeability. RESULTS The percentage (SD) rate of excretion of 51Cr-EDTA was 4.6 (2.6) in BS, 6 (2.4) in AS, 5.2 (1.9) in IBD, 5.56 (1.78) in SLE, and 2.3 (1) in healthy controls. (Analysis of variance: f=6.4, p=0.0002. BSv HC, AS vHC, SLE v HC significant.) CONCLUSION The intestinal permeability in BS was significantly more than that seen among the healthy controls. Similar results in all the diseased controls cast doubt on its specificity.

Quantiferon-TB Gold in tube assay for the screening of tuberculosis before and during treatment with tumor necrosis factor alpha antagonists

IntroductionThe usefulness of interferon-gamma (IFN-γ) release assays for tuberculosis screening before tumor necrosis factor-alpha (TNF-α) antagonists and for monitoring during treatment is a contraversial issue. The aims of this study were to determine whether TNF-α antagonists affect the results of the Quantiferon-TB Gold in-tube assay (QTF); to assess how QTF performs in comparison with the tuberculin skin test (TST) in rheumatoid arthritis (RA) patients who are about to start treatment with TNF-α antagonists, RA patients who are not candidates for treatment with TNF-α antagonists, rheumatology patients with confirmed current or past tuberculosis infection, and healthy controls, and to determine the specificity of the QTF test to differentiate leprosy patients, another group of patients infected with mycobacteria.MethodsThe 38 RA patients who were prescribed TNF-α antagonists, 40 RA patients who were not considered for TNF-α antagonist use, 30 rheumatology patients with a history or new diagnosis of tuberculosis, 23 leprosy patients, and 41 healthy controls were studied. QTF and TST were done on the same day, and both were repeated after a mean of 3.6 ± 0.2 months in patients who used TNF-α antagonists.ResultsTreatment with TNF-α antagonists did not cause a significant change in the QTF or TST positivity rate (34% versus 42%; P = 0.64; and 24% versus 37%; P = 0.22). Patients with leprosy had a trend for a higher mean IFN-γ level (7.3 ± 8.0) and QTF positivity (61%) than did the other groups; however, the difference was not significant (P = 0.09 and P = 0.43).ConclusionsTreatment with TNF-α antagonists does not seem to affect the QTF test to an appreciable degree. The higher IFN-γ levels in leprosy patients deserves further attention.

A survey of phenotype II in familial Mediterranean fever

OBJECTIVE Phenotype II in familial Mediterranean fever (FMF) is the onset of amyloidosis before the onset of FMF with its typical attacks, or as an isolated finding in a member of an FMF family. Its presence was investigated by looking for proteinuria among the asymptomatic relatives of patients with FMF complicated by amyloidosis and among the asymptomatic relatives of patients with juvenile chronic arthritis (JCA) complicated by amyloidosis, used as controls. METHODS The relatives of the index patients (13 with FMF and amyloidosis) and controls (6 with JCA and amyloidosis) were screened for proteinuria. Rectal biopsies were performed when proteinuria was significant (⩾300 mg/d). RESULTS 461 relatives were screened in the FMF group and 269 among the controls. Two of the FMF relatives and one JCA relative had no symptoms of FMF but had significant proteinuria. Rectal biopsy for amyloidosis was negative in all instances of significant proteinuria. CONCLUSION Phenotype II is uncommon among the relatives of patients with FMF and amyloidosis.

Pulmonary artery involvement in Behçet׳s syndrome: Effects of anti-Tnf treatment

OBJECTIVES Anti-TNF agents are being increasingly used in patients with Behçet׳s syndrome (BS) when conventional immunosuppressives fail. However, experience with anti-TNF treatment on pulmonary artery involvement (PAI) of BS is limited. METHODS A chart review revealed 13 patients with PAI (all men) treated with anti-TNF agents (12 infliximab and 1 adalimumab) following an inadequate response to immunosuppressives for 12.2 ± 9.5 SD months and 2 male patients who developed PAI while receiving infliximab for large vein thrombosis for 10 months and for parenchymal central nervous system involvement for 2 years, respectively. RESULTS The first patient developing PAI while receiving infliximab responded to cyclophosphamide and prednisolone but the second died with hemoptysis within 1 month. At the end of the survey, 6 of the 13 patients with PAI were continuing these agents for 25.5 ± 16.2 SD months with good response, 4 stopped anti-TNF treatment after a mean of 23 ± 9.8 SD months after achieving clinical and radiologic response and 1 patient with good response went to another center after receiving infliximab for 10 months and the remaining 2 experienced serious infections (lung tuberculosis and aspergillosis) necessitating early withdrawal. Two patients relapsed within 3 years after stopping anti-TNF agents and concomitant azathioprine. One developed mesenteric vein thrombosis necessitating bowel resection and the second developed new PAI that was controlled with cyclophosphamide and prednisolone after short courses of infliximab, adalimumab, and canakinumab. CONCLUSION Anti-TNF treatment seems to be effective for refractory PAI of BS but may not prevent its development. Relapses can be seen after withdrawal. Caution is required for their serious adverse effects.