Predictors of drug retention and treatment response in axial spondyloarthritis patients treated with certolizumab: real-life results from the HURBIO registry.

OBJECTIVES: To assess the real-life retention rate of certolizumab and factors related to retention of certolizumab. METHODS: We analysed all patients who received at least 1 dose of certolizumab and were registered in the HURBIO database. Patients with at least 1 control visit were included in efficacy analysis. Drug retention rates were calculated using the Kaplan-Meier method and predictors of drug retention was determined by Cox proportional hazard model. Factors predicting BASDAI50 response at first visit were analysed by the logistic regression analysis. Reasons of switching and discontinuation were also determined. RESULTS: A total of 325 (AS (76%), female 55%) patients were recruited. Median follow-up while receiving certolizumab was 13 (4.7-22.7) months. At 1 year, overall certolizumab retention rate was 72.5%. Predictors of poor certolizumab retention were: Current or ex-smoker [HR 1.11 (0.70-1.76), p=0.65], high CRP levels [HR 0.72 (0.45-1.16), p=0.18], biologic-naïve [HR 0.81 (0.49-1.32), p=0.39] and good BASDAI50 response at first control visit [HR 0.54 (0.30-0.96), p=0.04]. Mean duration from starting certolizumab to the first control visit was 3 (3-6) months. Predictors of poor BASDAI50 response: Presence of nr-axSpa [RR 2.12 (1.01-4.51), p=0.05], female gender [RR 2.14 (1.20-3.82), p=0.01] and history of biologic therapy [RR 3.52 (1.95-6.33), p<0.001]. The most common causes of drug switch were primary failure and drug side-effects. CONCLUSIONS: In this study, good BASDAI50 response at first visit seems to be a strong predictor of higher retention of certolizumab in patients with axial spondyloarthritis.

Retro-orbital granuloma associated with granulomatosis with polyangiitis: a series of nine cases.

Retro-orbital granuloma is a rare and devastating component of granulomatosis with polyangiitis (GPA). Current medical treatment protocols are falling short, and outcomes are poor. The aim of the study was to investigate the frequency, clinical features, and treatment outcomes of retro-orbital granuloma in patients with GPA. This is a retrospective, multi-centre study, which involves GPA cohorts from five different clinics. Data were extracted from patient charts including history, physical examination, radiological-laboratory-histological findings, and treatment protocols. Major clinical outcome measures were changes in the volume of the granuloma on comparative MRI, and visual acuity on repeated ophthalmologic examinations. Among 141 GPA patients, nine (five females and four males) were diagnosed with a retro-orbital granuloma. Median duration of disease was 8 years. Proptosis and diplopia were the dominant presenting symptoms (77%), followed by orbital pain (55%). Three out of nine patients had isolated retro-orbital granulomas, without other organ involvement of GPA. Five patients received conventional pulse steroid and pulse cyclophosphamide (CYC) as the first-line remission induction therapy. Four of these patients had progressive disease, and a regression in granuloma size was observed in one patient using this regimen. Two patients were already receiving immunosuppressants when they were diagnosed with retro-orbital granuloma. Six patients had been treated with RTX as the second-line remission induction therapy. None of these patients had progression following RTX therapy. Three patients underwent orbital decompression surgery. The indication for the decision for surgery was either progressive loss of vision or intractable pain. Standard first-line chemotherapy (CYC and steroids) was ineffective against retro-orbital granuloma associated with GPA. RTX could be an alternative in these cases. Surgical intervention may help to decrease the morbidity. Further prospective studies with greater patient numbers are needed to test the clinical efficiency of RTX as a first-line remission induction chemotherapy.

Novel cardiovascular risk factors and cardiac event predictors in female inactive systemic lupus erythematosus patients.

Systemic lupus erythematosus (SLE) is associated with severe and premature cardiovascular disease, which cannot be explained by traditional risk factors alone. This study aims to investigate novel cardiovascular risk factors and cardiac event predictors in inactive SLE female patients who do not have any major cardiovascular risk factors. Twenty-five inactive (SLE disease activity index score <4) SLE female patients and 22 healthy control women were studied. SLE patients with a history of diabetes mellitus, hypertension, hyperlipidemia, smoking, or coronary artery disease (CAD) were excluded. Venous blood samples were analyzed for lipid subfractions and novel cardiovascular risk factors such as lipoprotein (a), homocysteine, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and serum amyloid A (SAA) levels. Endothelial dysfunction was assessed by flow-mediated dilatation (FMD) from the brachial artery at baseline and during reactive hyperemia. SLE patients and controls were similar in terms of age (40+/-10 years vs 38+/-10 years, p = NS). No significant difference was found between the groups regarding family history of premature CAD, blood pressure, body mass index, lipoprotein (a), homocysteine, fibrinogen, SAA, apoprotein A-1 and B levels. Compared with the controls, SLE patients had higher levels of hs-CRP [median (range): 1.82 (0.02-0.98) vs 0.68 (0.02-0.35), p=0.04]. FMD was lower in SLE patients than controls (7.1+/-2.1 vs 11.4+/-1.2%, p<0.001). Increased levels of hs-CRP and decreased FMD were found in inactive SLE patients. Increased hs-CRP levels may reflect ongoing low-grade inflammation that could be a cause of impaired FMD in SLE patients. These findings suggest that SLE patients without traditional major cardiovascular risk factors may have increased risk of cardiovascular disease and future cardiac events.

B-type natriuretic peptide (BNP) levels in female systemic lupus erythematosus patients: what is the clinical significance?

Cardiovascular disease is a major cause of death in patients with systemic lupus erythematosus (SLE) especially during the late phase of the disease. This study was conducted to evaluate B-type natriuretic peptide (BNP) levels in female SLE patients without cardiac symptoms and to investigate whether BNP levels correlated with echocardiographic findings. We studied 59 women with SLE and 33 healthy women. SLE patients with history of cardiac disease, diabetes mellitus, hypertension, and other inflammatory diseases were excluded from the study. All subjects had a complete history and physical examination. Overall disease activity assessment in SLE patients at the time of the study were derived by calculation of SLE disease activity index (SLEDAI). BNP levels were determined, and transthoracic echocardiography were performed in all subjects. There was no difference between SLE patients and controls in terms of age, blood pressure, smoking status, plasma glucose, creatinine levels, and lipid profiles. Nine patients had SLEDAI score greater than 5. All subjects had an EF greater than 55%. Diastolic dysfunction was more frequent in lupus patients than in controls (15 [25.4%] vs. 2 [6%]; p = 0.022). BNP levels of SLE patients were significantly higher than controls (median 17.9 range [5-211] pg/ml vs. median 14.7 range [5-39.7] pg/ml; p = 0.033). Twenty-seven of the SLE patients (46%) and seven of the controls (21%) had BNP levels greater than or equal to 20 pg/ml (p = 0.019). There were no differences in BNP levels of SLE patients with and without diastolic dysfunction (median 17.8 range [5-117] pg/ml vs. median 18.5 range [5-211] pg/mL; p = NS). BNP levels were positively correlated with left atrium diameter (r (2) = 0.39, p = 0.001). BNP levels did not correlate with erythrocyte sedimentation rate/C-reactive protein levels, SLEDAI scores, total steroid dosage used, or other echocardigraphic parameters. BNP levels were increased in female SLE patients without cardiac symptoms as compared to healthy controls. Although none of the SLE patients in our study had clinical signs of ischemic heart disease, increased levels of BNP in SLE patients might be a reflection of a ischemic myocardial tissue.

Intensified, intermittent, low-dose intravenous cyclophosphamide together with oral alternate-day steroid therapy in lupus nephritis (long-term outcome).

The objective of this study is to evaluate the efficacy, toxicity, and long-term outcome of low-dose IV cyclophosphamid therapy with repeated frequent intervals in combination with oral and IV methylprednisolone in patients with SLE nephritis. In this study, 113 patients diagnosed as having SLE and glomerulonephritis were assessed in between 1993 and 2002, with a median follow-up of 44.1+/-41.2 months. The patients were treated with 500 mg IV cyclophosphamide and 1 g IV methylprednisolone together with 60 mg/alternate-day oral methylprednisolone in a given schedule. The clinical and laboratory data were evaluated. There were significant improvements in the clinical and the laboratory parameters. Six patients died shortly after being hospitalized due to the disease activity itself. Eight patients were excluded from the study because of low compliance. The renal functions of the patients remained stable throughout the therapy; only 16/99 patients needed one or two additional pulses. Temporary leukopenia developed in 18/99 patients and diminished with the suspension or prolongation of the IV cyclophosphamide administration. Gastrointestinal side effects, which needed extra medication, developed in 20 patients. Hematuria was observed in 6/99 patients. Menstrual abnormalities were seen in 7/99 patients. No serious infections due to immunosuppression were observed with the given regimen. Hypertension was observed in 13 patients (minimum of 140/90 mmHg, maximum of 190/110 mmHg) and controlled with angiotensine-converting enzyme inhibitors. Mild central obesity was observed in 15 of the patients. Leimyosarcoma was observed in one patient who died during the follow-up period. Therapy starting with the weekly low-dose IV cyclophosphamide to induce remission together with IV and oral steroids, followed by prolonged intervals with the same doses for 2 years, appears to be useful in preserving renal function without major side effects in patients with lupus nephritis, in comparison to other studies.

Wegener's granulomatosis: clinical and laboratory results of a university hospital study of 20 patients from Turkey.

The aim of this study was to evaluate the clinical and laboratory features, the treatment approaches, and the long-term outcome of patients with Wegener's granulomatosis (WG) who were followed up in our hospital. The hospital files of the patients with the diagnosis of WG who were followed up between the years 1985 and 2003 in Hacettepe University Hospital were retrospectively evaluated. Male/female ratio was 12:8. The mean age was 39 years (range 20-65 years). Constitutional symptoms and upper and lower airway involvement were seen in 95% of all patients. Renal and musculoskeletal symptoms were seen in 90 and 80% of the patients, respectively. Five patients were treated with oral monotherapy (three with methylprednisolone and two with cyclophosphamide). Three patients were given a combination of orally administered cyclophosphamide and methylprednisolone. Ten patients were treated with pulse cyclophosphamide and methylprednisolone combination together with oral alternate-day methylprednisolone therapy. The remaining two resistant patients were treated with pulse cyclophosphamide, methylprednisolone, and intravenous immunoglobulin combination together with oral alternate-day methylprednisolone. Four patients died because of the disease activity. Intravenous pulse therapies with oral, alternate-day methylprednisolone were well tolerated. Sixteen patients experienced long-term remission after immunosuppressive treatment. Eleven patients have been asymptomatic for more than 12 months. In five patients, residual symptoms persisted: constitutional symptoms and renal and respiratory tract symptoms in varying combinations. The demographic and laboratory findings in this trial were similar with those of the previous results. Alternate-day glucocorticoids plus cyctotoxic drugs may be beneficial in patients with WG.

Successful treatment of primary Sjögren's syndrome complicated with primary biliary cirrhosis and lung involvement.

A patient with primary Sjögren's syndrome complicated with primary biliary cirrhosis and lymphocytic interstitial pneumonia is presented. She was 38 years old and was admitted to our hospital for generalized pruritus, xerostomia, xerophthalmia, fatigue, and reticulonodular changes on her chest X-ray. With the findings of ground-glass attenuation and centrilobular nodules in high resolution computerized tomography, the diagnosis of lymphocytic interstitial pneumonia was made. Oral methylprednisolone 1 mg/kg/day and ursodeoxycholic acid 15 mg/kg/day were started. At the 6th month follow-up, she had no complaints, and pulmonary function tests and high resolution computerized tomography were normal. This is the first case of Sjögren's syndrome, primary biliary cirrhosis and lymphocytic interstitial pneumonia in the English literature.

Serum adenosine deaminase activities during acute attacks and attack-free periods of familial Mediterranean fever.

BACKGROUND: Familial Mediterranean Fever (FMF) is a systemic relapsing autoinflammatory disorder. Adenosine deaminase (ADA) is an enzyme widely distribute in tissues and body fluids. Circulating levels of ADA have been shown to increase in several inflammatory conditions. This study was designed to evaluate the serum ADA in patients with FMF during acute attacks and attack-free periods. METHODS: The study groups comprised 23 FMF patients in attack-free period (male/female: 11/12), 30 FMF patients in attack period (male/female: 11/19) and 20 healthy control (male/female:10/10). The groups were similar for age, gender and disease duration. RESULTS: The mean age of FMF patients in attack-free period, patient with acute attack were 34.3+/-11.7 and 29.4+/-11.1 respectively. The disease durations were 13.1+/-10.2 and 8.2+/-7.6 years for patients in attack-free periods and patients with acute FMF attack, respectively. Patients with acute attack had significantly higher ADA levels than both patients with attack-free periods and healthy controls (for each, p<0.001). CONCLUSION: In this study we demonstrated that FMF patients with acute attacks had higher serum ADA levels than attack-free periods and healthy controls. It is likely that ADA may have a role in the cytokine network of the inflammatory cascade of FMF. Also, elevated ADA levels may be a part of the activated Th1 response in the disease. ADA may be used as a supportive marker to differentiate FMF attacks from attack-free periods. Further larger-scale studies are needed to support this result.

Pneumocystis carinii pneumonia in a rheumatoid arthritis patient treated with adalimumab.

Patients with rheumatoid arthritis (RA) have an increased risk of infection as a result of alterations in immune regulation, debility, and comorbid illnesses. TNF-alpha is of central importance in the pathophysiological responses to infection and inflammation, and plays a crucial role in host defence. Pneumocystis carinii is an opportunistic pathogen that commonly affects individuals with inadequate T-cell mediated immune response. Patients with acquired immune deficiency, as well as those receiving immunosuppressive drugs for various conditions have an increased risk of P. carinii pneumonia (PCP). We report the development of PCP in a woman with RA shortly after the initiation of anti-TNF-alpha treatment with adalimumab.

Association of drug transporter gene ABCB1 (MDR1) 3435C to T polymorphism with colchicine response in familial Mediterranean fever.

OBJECTIVE: Colchicine is a mainstay of treatment in familial Mediterranean fever (FMF); however, 5%-10% of patients do not respond to colchicine. Adenosine triphosphate-binding cassette subfamily B member 1 (ABCB1 or MDR1) is a drug transporter that extrudes colchicine out of cells. ABCB1 gene 3435C to T polymorphism has been demonstrated to alter MDR1 expression in mononuclear cells. Thus, the amount of MDR1 in mononuclear cells may alter response to colchicine. We investigated the association between MDR1 3435C to T polymorphism and colchicine response in patients with FMF. METHODS: Patients (n = 120) were examined for colchicine responses. ABCB1 gene 3435C to T genotypes were determined to analyze associations with colchicine resistance. RESULTS: Ninety-eight patients were evaluated as responders and 22 as nonresponders. The distributions of ABCB1 CC, CT, and TT genotypes were significantly different between responsive and nonresponsive groups (chi-square = 6.86, p = 0.032). Colchicine resistance was significantly higher in patients harboring the C allele than in patients with TT genotype (odds ratio 9.71, 95% CI 1.58-58.76). Similarly, the mean colchicine dose to prevent remission was significantly lower in the TT group compared with subjects with the C allele (p = 0.014). CONCLUSION: Our study revealed an association between 3435C to T polymorphism and colchicine response in patients with FMF. Patients with the TT genotype for the ABCB1 3435C to T variant responded better to colchicine in terms of treatment efficacy and colchicine dose requirements.