Long-term drug survival of biological agents in patients with rheumatoid arthritis in clinical practice.

OBJECTIVES: To assess and compare the long-term drug survival (time to drug discontinuation) of biological agents (BA) in patients with rheumatoid arthritis (RA) in clinical practice. Factors associated with discontinuation of BAs were also investigated. METHOD: We conducted an observational longitudinal study of RA patients taking BAs from 1999 to 2013. The primary endpoint was BA discontinuation due to: adverse drug reactions (ADRs), inefficacy, and other causes. Incidence rates of discontinuation (IRs) per 100 patient-years were estimated using survival techniques. Comparisons between BA discontinuation rates and other associated factors were made using Cox regression models. RESULTS: We included 851 courses of BA therapy (1869 patient-years). Adalimumab (33%) was the BA most frequently used, followed by etanercept (24.4%), infliximab, and rituximab. Treatment was suspended in 558 cases [IR 29.8, 95% confidence interval (CI) 27-32]. In the first year of therapy 68% continued on BAs, and after 10 years the retention rate did not exceed 10%. The IR due to inefficacy was 12.1 (95% CI 10.6-13.8) and the IR of ADRs was 13.6 (95% CI 12-15). The unadjusted IR was higher for rituximab than for tumour necrosis factor (TNF) antagonists. In multivariate analysis, infliximab was the BA with the highest risk of discontinuation, compared to adalimumab. Calendar period, taking subsequent courses of BAs, concomitant therapy, and specific comorbidities were also independent factors associated with discontinuation. CONCLUSIONS: After several years of BA treatment in clinical practice, the survival rate was low, mainly as a result of ADRs and inefficacy. We also found differences between the discontinuation rates of BAs and other clinical factors that modify their survival.

Study of association of CTLA4 gene variants to non-anterior uveitis.

This study was undertaken to investigate the possible genetic association of functional CTLA4 polymorphisms with susceptibility to non-anterior uveitis. Four hundred and seventeen patients with endogenous non-anterior uveitis and 1517 healthy controls of Spanish Caucasian origin were genotyped for the CTLA4 polymorphisms rs733618, rs5742909 and rs231775, using predesigned TaqMan(©) allele discrimination assays. PLINK software was used for the statistical analyses. No significant associations between the CTLA4 polymorphisms and susceptibility to global non-anterior uveitis were found. It was also the case when the potential association of these genetic variants with the anatomical localization of the disease, such as intermediate, posterior or panuveitis, was assessed. Our results do not support a relevant role of these CTLA4 polymorphisms in the non-anterior uveitis genetic predisposition.

Long-term use of antimalarial drugs in rheumatic diseases.

OBJECTIVES: To evaluate long-term use of antimalarial drugs and to analyse all causes of discontinuation. METHODS: This is a retrospective study of a cohort of rheumatic diseases patients on antimalarials, during a maximum period of 17.5 years. Case was defined as antimalarial treatment discontinuation due to: a) lack of efficacy, b) adverse events, and c) other causes. Survival techniques were used to estimate the incidence rate (IR) per 1,000 patient-years with the 95% Confidence Interval (95% CI) of antimalarial treatment discontinuation. Cox regression models were conducted to evaluate possible associated factors to antimalarial discontinuation. RESULTS: One thousand, two hundred and ninety-one medical records were reviewed, and 778 patients were included. Patients started 869 different courses of treatment, with a total follow-up of 2,263 person-years. The IR of global discontinuation was 204 (95% CI 186-224). Fifty-two per cent of the treatments stopped were related to adverse events, 14% to lack of efficacy; and 34% to other reasons (refusal to take medication, ocular comorbidity, remission, or pregnancy). Adverse events discontinuations were related to non-ophthalmologic reasons in 54.5% (gastrointestinal, neuro-psychiatric, skin problems), and to ophthalmologic adverse events in 45.5%. Nine patients suffered definite presence of antimalarial retinopathy (IR: 3.97 [IC 95%: 2.06-7.62]) and one of them irreversible loss of vision (IR: 0.44 [IC 95%: 0.06-3.12]). Women, increasing age, and chloroquine vs. hydroxychloroquine use, increased the risk of discontinuation due to ophthalmologic adverse events. CONCLUSIONS: Results suggest that antimalarials have a good balance between benefit and risk. However, we noted a number of discontinuations due to both inefficacy and adverse events. The potential for an unusual but serious ophthalmologic toxicity emphasises the importance of close ophthalmologic monitoring.

[Treatment with venlafaxine extended release for climacteric women with depression or anxiety diagnosis. An open-label study]. / Tratamiento con venlafaxina clorhidrato de mujeres climatéricas con diagnóstico de ansiedad o depresión. Estudio abiero.

INTRODUCTION: The objective of this observational study was to assess under real clinical practice conditions the effectiveness and safety of venlafaxine extended release in anxiety-depressed and hormone-related symptoms in climacteric women with anxiety or depressive disorders. METHODOLOGY: Observational, prospective, open-label, multicenter, 24-week study, carried out in Spain. A sample of 45 outpatients, adult women between 45 and 55 years of age, diagnosed of depressive disorder, generalized anxiety disorder or social anxiety disorder were analyzed. Venlafaxine extended release was administered for 24 weeks at doses according to the investigator's clinical criteria. RESULTS: Of the total of 45 patients who were included in the study, 43 (95.6%) completed it. The patients' age range was of 47 to 55 years old, median of 50 and mean of 50.82. The clinical condition evolution was assessed with the evaluation scales scores: Blatt-Kuppermann Menopausal Index, Hamilton Depression Rating Scale, Hamilton Anxiety Scale and Clinical Global Impression. During the 24-week period, a significant decrease in the different scales scores showed a clinical improvement. CONCLUSIONS: The results achieved show that treatment with venlafaxine extended release significantly improved the clinical condition of climacteric patients with anxiety or depressive disorder. If these results are confirmed with placebo-controlled clinical trials, they will support the utility of Venlafaxine extended release in this kind of patients.

Treatment of refractory posterior uveitis with infliximab: a 7-year follow-up study.

OBJECTIVE: To describe, in a 7-year follow-up study, the use of infliximab in patients with refractory posterior uveitis and scleritis. METHODS: A 7-year follow-up case series study was performed. Patients with posterior uveitis and scleritis refractory to conventional therapies (steroids and at least one immunosuppressive agent) were included. Three infliximab intravenous doses of 5 mg/kg were administered at weeks 0, 2, and 6. Further infusions were allowed in patients undergoing a relapse of the uveitis after initial remission. All patients were followed up for at least 8 months. We defined uveitis improvement as an increase in the best-corrected visual acuity or an objective and significant improvement in retinal exudates and/or haemorrhages, cystoid macular oedema (CME), and vitreous haze. Infliximab-related adverse events, final prednisone doses, and the number of immunosuppressive agents used were recorded. A descriptive analysis was performed. RESULTS: A total of 11 patients (17 eyes were affected at baseline) were included, 63% were women, the mean age was 43+/-14 years, and the median follow-up was 80 months (p25-p75: 50-80). After infliximab treatment, six eyes maintained their basal visual acuity, nine eyes showed improvement, and two worsened (in the two patients diagnosed with choroiditis). Vitreous haze, active retinal vasculitis, and CME, but not chorioretinal lesions, improved in all patients. All patients tapered their daily steroid dose and the number of immunosuppressive agents. No infliximab-related adverse events were reported. CONCLUSIONS: Infliximab could be an effective and safe treatment in patients with posterior uveitis and scleritis refractory to conventional therapy.

Ocular inflammatory signs observed in a cohort of Spanish patients with Behçet disease and ocular inflammation.

PURPOSE: To study the clinical characteristics of a cohort of Spanish patients diagnosed with Behcet disease and who also presented ocular inflammation. METHODS: Thirty cases of Behçet disease were studied retrospectively. The authors studied age distribution, distribution by sex, clinical course, laterality, type of uveitis, secondary glaucoma, corneal involvement, hypopyon, iris-lens synechiae, secondary cataract, cystoid macular edema (CME), and papillitis (optic neuritis). RESULTS: Fourteen of the patients were men and 16 were women (ratio 0.875:1). The mean age of the patients was 35.24 years (+/-10.917; 21-61 years). In 23 patients, the disease course was recurrent. In 9 patients, the disease manifested unilaterally. In 5 patients showing unilateral onset, the contralateral eye became affected. In 2 of the 30 patients, uveitis exclusively affected the anterior segment. In 8 patients, uveitis was solely posterior. There was one case of intermediate uveitis. The remaining 19 patients showed panuveitis. Three had focal chorioretinitis. One had diffuse chorioretinitis. Fifteen showed signs of diffuse vasculitis. Eight patients showed focal vasculitis. CONCLUSIONS: Women were slightly more affected than men, although the authors found no significant correlation between sex and the clinical variables examined. Apart from one unexpected case of intermediate uveitis, the observations are similar to those reported for other patient series.

Differences between rheumatology attending physicians and training residents in the management of rheumatoid arthritis in Spain.

OBJECTIVE: To evaluate the variability in the characteristics and management of rheumatoid arthritis (RA) patients between rheumatology attending physicians and training residents in Spain. METHODS: A retrospective medical record (MR) review was performed in a probabilistic sample of 1379 RA patients from 46 centres distributed in 16 of the 19 autonomous communities (AC) of Spain. RA patients' sociodemographic and clinical characteristics, healthcare resources use, and their single responsible physician's (defined as an identifiable single physician who attended the patient in more than 75% of visits) characteristics were recorded following a standardized protocol. Multivariate analyses were performed to assess differences in the characteristics and management of RA patients between attending physicians and training residents. RESULTS: A total of 1205 RA patients had a single responsible physician and were analysed (nearly 75% women with rheumatoid factor positive and more than 25% with persistent active disease), 49 of whom were followed by training residents and 1156 by attending physicians. In the multivariate analyses, irrespective of patient and disease characteristics, training residents' patients reported more hospital admissions, laboratory tests, and imaging techniques compared to attending physicians. Training residents also less frequently used combined therapy with disease-modifying antirheumatic drugs (DMARDs). CONCLUSION: Training residents and attending physicians differ in RA patients' care. More efforts in training programmes are necessary to guarantee proper RA management and to improve the profile of the future rheumatologists.

[Articular diseases and uveitis]. / Enfermedades articulares y uveítis.

Ocular inflammation is a common clinical manifestation related to several autoimmune systemic disorders, specially spondyloarthropaties. In this group, there are different clinical diseases that are related to special uveitic patterns. Several discriminative patterns have been defined that closely link uveitis with certain systemic or ophthalmic diseases. Unilateral recurrent anterior acute uveitis is the most frequent form of uveitis related to spondyloarthropaties, and is sometimes the initial manifestation of an undiagnosed spondyloarthropaty. The collaboration of ophthalmologists, rheumatologists and internal medicine specialists is very important for the correct management and treatment of these patients.

[Incidence and characteristics of tuberculosis in patients with autoimmune rheumatic diseases]. / Incidencia y características de la tuberculosis en pacientes con enfermedades reumáticas autoinmunes.

OBJECTIVE: To describe the incidence and characteristics of the infection caused by Mycobacterium tuberculosis in patients with autoimmune diseases. PATIENTS AND METHODS: Searching in the database of the department at our institution, all new cases of tuberculosis from 1991 to 2000 were identified in patients with autoimmune diseases; the total follow-up time was calculated as the difference between first and last visits. Time with immunosuppressive drug therapy was obtained for patients with rheumatoid arthritis from a database oriented to the longitudinal follow-up of these patients. The incidence density was calculated as the quotient between the absolute frequency of cases and the sum of individual periods at risk for each subgroup. RESULTS: Fifteen cases of tuberculosis were identified from 3,634 risk patients followed for an accumulated period of 9,795 years (overall incidence 153 per 100,000 patients-year). Fourteen patients were receiving disease-modifying drugs and eleven were receiving corticosteroids at diagnosis. The location of tuberculosis infection was the lung for 33.3% of cases. The incidence by drugs in patients with rheumatoid arthritis was 143 per 100,000 patients-year with methotrexate, 2,703 per 100,000 patients-year with azathioprin, 7,692 per 1,000 patients-year with cyclophosphamide, and 4,878 per 100,000 patients-year for anti-TNFalpha. CONCLUSIONS: Compared with the general population, the incidence density of tuberculosis is increasing in our population, with a higher frequency of extrapulmonary involvement. The incidence density is variable among patients with rheumatoid arthritis depending upon the used drugs.

Lag time between onset of symptoms and access to rheumatology care and DMARD therapy in a cohort of patients with rheumatoid arthritis.

OBJECTIVE: To study demographic and clinical variables associated with a longer delay in disease modifying antirheumatic drug (DMARD) therapy initiation in a cohort of patients with rheumatoid arthritis (RA). METHODS: We studied 527 new RA patients (74.3% female, median age at symptom onset 55 yrs) in a hospital setting who fulfilled the ACR criteria for the diagnosis of RA. Demographic, clinical, laboratory, and treatment variables were collected longitudinally into a computerized research database. Risk factors for delay in use of DMARD therapy and first evaluation by a rheumatologist were analyzed using a Cox regression model. RESULTS: The median lag time between symptom onset and first rheumatologist encounter was 17 months and between onset of symptoms and first DMARD therapy 19 months. Variables associated with longer delay to DMARD therapy were the lag time between symptom onset and first rheumatologist visit (RR 0.73, 95% CI 0.71-0.76) and years of education. Variables associated with longer delay in first visit with rheumatologist were swollen/tender joint count, age at symptom onset, home support, labor force status, marital status, and years of education. CONCLUSION: Awareness of factors associated with a longer delay in access to rheumatology care and DMARD therapy may help break down barriers that prevent their early access, irrespective of patient age, socioeconomic status, initial symptoms, or need for treatment.

Undiagnosed spondyloarthropathy in patients presenting with anterior uveitis.

OBJECTIVE: To investigate patients with formerly undiagnosed underlying spondyloarthropathy (SpA) in a series of anterior uveitis (AU) cases and to describe the rheumatologic and ophthalmologic characteristics of these patients. METHODS: Patients with anterior uveitis referred to the Uveitis Clinic between January 1992 and December 1998 who had a final diagnosis of SpA were included in the study group. The diagnosis of SpA was based on current diagnostic criteria. Patients were classified into 2 groups: formerly diagnosed, or undiagnosed SpA before attendance at the uveitis clinic. Demographic features, clinical symptoms, ophthalmologic characteristics, and laboratory tests were collected prospectively in each patient. A regression logistic model was applied. RESULTS: We evaluated 514 patients with anterior uveitis; 117 (22.7%) had some type of SpA. Ankylosing spondylitis was the most frequent diagnosis (64.1%). More than half the patients (53%) were diagnosed with SpA after an episode of uveitis; the percentage was up to 90.9% in undifferentiated SpA. Clinically, the formerly diagnosed and undiagnosed groups were quite similar, inflammatory low back pain being the most frequent symptom in both groups. Radiological sacroiliitis was less common and with a lower grade in the formerly undiagnosed group. Acute recurrent unilateral anterior uveitis was the most frequent clinical pattern in the group as a whole (68.3%), observed in all subgroups, except for inflammatory bowel disease related SpA, which presented panuveitis as the most frequent pattern. CONCLUSION: SpA was the most frequent systemic disease related to anterior uveitis, seen in more than 50% of our SpA cases diagnosed after an episode of uveitis. The undiagnosed SpA patient is generally an atypical case, with a shorter clinical evolution and less radiological damage.

[ACE inhibitor therapy of hemodialyzed patients]. / Hemodializált betegek ACE-gátló kezelésének gyakorlata.

Authors studied the daily dose of angiotensin converting enzyme inhibitor captopril and enalapril in patients with hypertension on regular hemodialysis of three hemodialysis units, and the relationship between the daily doses of angiotensin converting enzyme inhibitors and the number of simultaneously used other antihypertensive agents in the same patients. 104 out of 133 hemodialysed patients were treated with antihypertensive agents, 53 patients received angiotensin converting enzyme inhibitor. The data of 23 captopril treated patients in 3 dialysis units and data of 17 enalapril treated patients in 2 dialysis units were used as the basis of the study. The difference between the average daily doses of captopril applied at the different hemodialysis units was significant (111, 61 and 26 mg/day). However the difference between the average doses of enalapril was not significant (18 and 12.9 mg/day). The correlation was found to be significant between the dose of captopril and the number of simultaneously used antihypertensive agents: r = 0.46, p < 0.05. The correlation was also significant between the dose of enalapril and the number of combinations of other antihypertensive agents: r = 0.50, p < 0.05. These relations and the analysis of antihypertensive therapy of 4 patients, receiving the largest doses of captopril suggest that larger doses of angiotensin converting enzyme inhibitors were used in the more resistant hypertensive patients, where more antihypertensive agents were needed to be administered to control the blood pressure.

[Water intoxication in pulmonary tuberculosis complicated by aspergillosis]. / Vízmérgezés aspergillosissal szövödött tüdötuberculosisban.

The authors found a serum sodium level of 113 mmol/l in a 70 year old confused male patient with cachexia and fever, which level rised to 125 mmol/l as a result of hypertonic sodium chloride and furosemide therapy, resulting in improving sensorium. At the same time the urine osmolality (235 mOsm/kg) was high compared to the serum osmolality (258 mOsm/kg). The physical and radiological examination showed bilateral pneumonia. The patient died in acute circulatory insufficiency. At the autopsy miliary pulmonary tuberculosis with superinfection by aspergillosis was proved. The authors discuss the possible mechanisms of water intoxication occurring with lung diseases and the difficulties regarding the diagnosis and therapy of aspergillosis.

[Repeated serious water intoxication in an aged patient. (Data on the relationship between the inappropriate antidiuretic hormone syndrome and the atrial natriuretic factor)]. / Ismétlödö súlyo vízmérgezések egy idös betegben (Adatok az "inappropriate antidiuretic hormone" syndroma és az atrialis natriureticus factor kapcsolatához).

An old women was in an 8-year-period 9 times admitted to the hospital because of severe mental disturbances. The average serum sodium concentration was 126.25 +/- 2.43 mmol/l at the admissions; it increased to 139.44 +/- 1.40 mmol/l after intravenous infusion of hypertonic solutions accompanied with the disappearance of the mental disturbances. The patient was usually chronically hyponatremic due to the increased water intake and the insufficient water excretion. The latter was induced by the augmented vasopressin levels. The remarkable feature of the syndrome of inappropriate antidiuretic hormone secretion was its association with lowered blood level of atrial natriuretic factor accompanied by sodium, and volume depletion. Discontinuation of the exaggerated water intake resulted in the elimination of the permanent hyponatremia; no episode of water intoxication occurred during the last 3 and 1/2 years.

[Clinical spectrum of distal renal tubular acidosis and its study with bicarbonate loading]. / A distalis renalis tubularis acidosis klinikai spectruma és vizsgálata bicarbonatterheléssel.

Authors attempted to review the clinical spectrum of distal renal tubular acidosis on the basis of analysing the records of 11 patients. Distal renal tubular acidosis was associated with chronic renal failure of different severity and with tubulointerstitial diseases in the two-third of patients in whom histologic studies were also performed. The disorders caused in certain cases hypokalemia and hyperkalemia in the others, the concentrating insufficiency was characteristic leading in exceptional cases to nephrogenic diabetes insipidus and the clinical picture was accompanied also by osteomalacia. Authors describe their own method of bicarbonate loading, obtaining by its use very high values of 78.65 +/- 11.28 (p < 0.005) mmHg of urine minus blood pCO2 in 6 healthy subjects. On the other hand, in 6 distal renal tubular acidosis patients no such difference in the pCO2 values could be found. The knowledge of the clinical spectrum of the distal renal tubular acidosis may enhance the recognition and treatment of the disorder.

[Effect of calcitriol, a vitamin D compound, in bone disease associated with distal renal tubular acidosis]. / D-vitamin-készítmény (calcitriol) hatása distalis renalis tubularis acidosishoz társuló csontbetegségben.

In a 47-year-old female patient distal renal tubular acidosis (dRTA) led to the development of osteomalacia following 13 years of the first episode of hypokalemic respiratory paralysis and 7 years of KHCO3 treatment. In spite of the musculoskeletal disability, intense bone pain and myopathy, the values of serum calcium (Ca++) and phosphorous (P) showed minimal deviation from the normal levels. The bone scintigraphy was the first indicator of the bone disease. As the disease progressed the serum level of alkaline phosphatase increased gradually and 25-hydroxyvitamin-D level decreased and bone scintigraphy showed multiple areas of increased radioisotope uptake. By that time the patient's condition deteriorated severely, she became almost unable to walk. Rocaltrol (calcitriol) therapy led to dramatic clinical improvement and the complete resolution of the laboratory values. When the alkaline therapy of dRTA does not prevent the development of osteomalacia, administration of a modern vitamin-D preparation can result complete healing of the bone disease.

[Circadian rhythm of blood pressure in hypertension treated with enalapril and other drugs]. / A vérnyomás napi ritmusa enalaprillal és más gyógyszerekkel kezelt hypertoniában.

Twenty-four-hour "ambulatory blood pressure monitoring" (ABPM) was performed during the day at every 30 min and during the night at every 60 min in 38 persons admitted to the hospital. The subjects were divided into four groups: Group 1. healthy subjects (11); Group 2. essential hypertensive patients (7) before and during enalapril treatment; Group 3. patients with essential hypertension (10) treated with different antihypertensive drugs and Group 4. renal patients treated as in Group 3. Normal circadian rhythm was found in the healthy subjects and in the patients with essential hypertension, but no rhythm could be demonstrated in the renal patients. The high blood pressure decreased in response to enalapril in 7 patients without any decrease in the circadian rhythm. It was concluded that antihypertensive therapy does not abolish the circadian rhythm if there is any--and does not restore if it is lacking. The chances of the diagnostic use of circadian blood pressure rhythm are not impaired by the antihypertensive treatment.

[Coxsackie B4 and cytomegalovirus in patients with insulin-dependent diabetes]. / Coxsackie B4 y citomegalovirus en pacientes con diabetes insulín dependiente.

The purpose of this work is to analyze the potential relationship between infection by Coxsackie and cytomegalovirus and the appearance of insulin-dependent diabetes (IDD). We have assessed complement fixing (CF) antibodies against both viruses in 22 samples of serum from other individuals, among which 11 were patients with a recent diagnosis of IDD--less than 3 months of evolution--(GP) and the remainder 11, supposed healthy individuals with similar age, sex and socioeconomic level (GC). In addition, the presence of anti-pancreatic islets antibodies (ICA) was assessed in 22 serum samples using the indirect immunofluorescence reaction. We have not observed any relationship between the presence of Coxsackie B or CMV antibodies and the appearance of IDD, since although the seroprevalence against CMV was higher in GP than in GC, such difference was not statistically significant. With respect to ICAs, they were only present in the GP samples as expected. Given the small size of the sample, this results are not conclusive and larger series need to be studied.