The impact of tocilizumab on anxiety and depression in patients with rheumatoid arthritis.

BACKGROUND: Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. MATERIALS AND METHODS: Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. RESULTS: Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P < .01). CONCLUSIONS: This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA.

Clinical relevance of bilateral pleural effusion in patients with acute pulmonary embolism.

BACKGROUND: The clinical relevance of bilateral pleural effusion (BPE) in patients with acute pulmonary embolism (PE) is unclear. AIMS: To describe characteristics of patients with acute PE that present with BPE. METHODS: Patients with acute PE were retrospectively analysed and divided into three groups: without pleural effusion, unilateral pleural effusion and bilateral effusion. Clinical, laboratory and radiological characteristics were compared between the three groups. RESULTS: The study population (n = 343) consisted of unilateral effusion group (n = 83), BPE group (n = 94) and without effusion group (n = 166). Several variables were noted in higher proportion (%), in the BPE group in comparison to both the unilateral effusion and without effusion groups: heart failure (17.0 vs 7.2 vs 6.7, P = 0.017), hypoalbuminaemia (59.3 vs 39.5 vs 25.6, P ˂ 0.001), PE occurrence in-hospital setting (51 vs 25.6 vs 15.1, P ˂ 0.001), major operation (31 vs 19.2 vs 15.2, P = 0.01) and mechanical ventilation (13.0 vs 4.9 vs 4.2, P = 0.019). Norton scale scores were found to be lower among patients with BPE in comparison to both patients with unilateral and without pleural effusion (15.55 vs 16.92 vs 17.36, P = 0.006). After adjusting confounding variables, patients with BPE have lower probability for in-hospital survival in comparison to both patients with unilateral pleural effusion (odds ratio = 0.30, 95% confidence interval 0.12-0.79), and patients without pleural effusion (odds ratio = 0.26, 95% confidence interval 0.11-0.61). CONCLUSIONS: BPE in patients with acute PE may have significant clinical implications. It may signify serious underlying comorbidities which contribute to higher in-hospital mortality in comparison to both patients with unilateral pleural effusion and patients without pleural effusion.

A Study of the Efficacy and Safety of Subcutaneous Injections of Tocilizumab in Adults with Rheumatoid Arthritis.

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

All-cause hospitalizations in systemic lupus erythematosus from a single medical center in Israel.

OBJECTIVE: Clinical features of systemic lupus erythematosus (SLE) have been described from different geographical regions in the world. The aim of this study was to obtain local and contemporary data on all-cause hospitalizations of SLE patients in an Israeli Medical Center. METHODS: This is a retrospective observational single-center study. Revision of medical records of hospitalized lupus patients during 5-year period (January 2012-December 2016) was performed. RESULTS: A total of 61 lupus patients and 138 hospitalizations were identified. Female-to-male ratio was 9:1. Average age was 42.5 years. Average disease duration was 14.58 years. Mean SLICC/ACR damage index was 0.75. The majority of patients were treated with lupus medications (47, 77%). The most common lupus medications were hydroxychloroquine (40, 65.5%), prednisone (25, 40.9%), and azathioprine (9, 14.75%). The most common reasons for hospitalization were disease flare (28, 20.3%), pregnancy and labor (26, 18.9%), and infection (19, 13.8%). The average length of hospitalization for all patients was 6.65 days. No fetal morbidity was recorded, and there was one event of maternal morbidity. There were no cases of acute coronary events. There were six ICU admissions (4.35%). Two admissions (1.45%) were complicated by hospital-acquired infection. Three patients died (2.17%) during hospital stay. CONCLUSIONS: This survey from a single Israeli medical center revealed low rates of pregnancy complications, coronary events, and nosocomial infections in hospitalized lupus patients. Further studies are required to determine whether these findings reflect local disease expression or it may remark global trend of decrease in lupus complications.

Effect of Tocilizumab on Fatigue and Bone Mineral Density in Patients with Rheumatoid Arthritis.

BACKGROUND: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients. OBJECTIVES: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. METHODS: In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. RESULTS: The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data. CONCLUSIONS: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.

The impact of concomitant fibromyalgia on visual analogue scales of pain, fatigue and function in patients with various rheumatic disorders.

OBJECTIVES: To evaluate the impact of concomitant fibromyalgia on the rating of pain, fatigue, and dysfunction, in patients with various rheumatic disorders. METHODS: A cross-sectional study was carried out in a hospital-based rheumatology unit. Standard clinical and laboratory data were obtained and all patients completed questionnaires on pain, fatigue, and daily function. The rate of concomitant fibromyalgia was estimated using the 1990 American College of Rheumatology (ACR) classification criteria for fibromyalgia and the analysis concentrated on visual analogue scales (VAS). RESULTS: Six hundred and eighteen visits of 383 patients with inflammatory as well as non-inflammatory rheumatic disorders were analyzed. Concomitant fibromyalgia was noted in 74 patients (23% of the cohort). Patients with rheumatic diseases and concomitant fibromyalgia had significantly higher mean VAS scores for pain, fatigue, and function (79±17, 81±18, 80±18, respectively) as compared to patients who had no features of fibromyalgia (47±28, 50±29, 44±30 respectively; all p values <0.001). The scores reported by patients with rheumatic diseases and concomitant fibromyalgia were similar to the scores obtained from patients with primary FM. CONCLUSIONS: Concomitant FM is common both among patients with inflammatory and patients with non inflammatory rheumatic disorders. Concomitant FM has a remarkable impact on the severity of symptoms and, moreover, patients with concomitant FM exhibit extreme and significantly distinct levels of pain and fatigue which is as severe as that reported by patients with primary FM. It seems that fibromyalgic features dominate and become the main cause of morbidity in rheumatological patients with concomitant FM.

Visual Analogue Scales of Pain, Fatigue and Function in Patients with Various Rheumatic Disorders Receiving Standard Care.

BACKGROUND: Pain, fatigue and functional disability are common key outcomes in most rheumatologic disorders. While many studies have assessed the outcomes of specific disease states, few have compared the outcomes of various rheumatic diseases. OBJECTIVES: To assess how the intensity and rating of pain, fatigue and functional disability vary among groups of patients with various rheumatic disorders receiving standard care. METHODS: In a cross-sectional study conducted in a hospital-based rheumatology unit, standard clinical and laboratory data were obtained and all patients filled out questionnaires on pain, fatigue and daily function. The analysis concentrated on visual analogue scales (VAS) using specific statistical methods. RESULTS: A total of 618 visits of 383 patients with inflammatory as well as non-inflammatory rheumatic disorders were analyzed. Fibromyalgia patients had significantly higher VAS scores compared to all other groups. On the other hand, patients with polymyalgia rheumatica demonstrated significantly lower VAS scores compared to all other groups of patients. Patients with psoriatic arthritis also demonstrated relatively low VAS scores. VAS scores were lower in patients with inflammatory disorders as compared to patients with non-inflammatory disorders. CONCLUSIONS: Our results suggest a spectrum of outcome intensity in various rheumatic disorders receiving standard care, ranging from fibromyalgia patients who report distinctive severity to patients with inflammatory disorders who are doing relatively well as compared to patients with non-inflammatory disorders. The findings emphasize the need to explore the underlying mechanisms of pain and fatigue in patients with non-inflammatory rheumatic disorders.

Can fibromyalgia be associated with whiplash injury? A 3-year follow-up study.

The objective of this study is to assess the long-term outcome and natural history of a cohort of patients with whiplash injury regarding the development of fibromyalgia. Of the 153 patients who were admitted to the emergency room after whiplash injury in 2004, 126 were reassessed 3 years later. Also, 33 of 53 patients from the original control group of hospitalized patients with fractures were reevaluated. Patients were interviewed by phone and by written forms using a detailed questionnaire. Patients who complained of musculoskeletal symptoms were invited and examined. The study group included 68 men and 58 women, with a mean age of 50.1 ± 9.7. The control group included 19 men and 14 women with a mean age of 44.2 ± 10.3. Follow-up period did not differ significantly between the groups 38.3 ± 2.3 vs. 36.4 ± 4.2 months. At the end of the follow-up period, three patients in the study group compared with one patient in the control group were diagnosed as having fibromyalgia; all of them were women. The rate of new onset widespread pain increased with time in both groups. Symptoms of dizziness, headaches, fatigue and sleep disturbances improved, as well as the quality of life (QOL) and the Fibromyalgia Impact Questionnaire (FIQ) scores. Insurance claims continued to be more prevalent in the control group. The results of this extended follow-up study confirm previous short-term results showing that whiplash injury and road accident trauma are not associated with an increased risk of fibromyalgia.

99m Tc-albumin nanocolloid joint scintigraphy in rheumatoid arthritis patients who are in clinical remission - is remission real ?

OBJECTIVES: To make a comparison between the clinical data and the imaging results with 99mTc-nanocolloid scintigraphy in rheumatoid arthritis (RA) patients considered to be in remission. METHODS: Forty RA patients found to be in clinical remission according to the ACR and the EULAR (DAS28<2.6) criteria were studied. The group included 29 females and 11 males with a mean age of 60.8+/-13.5 years (range 22-86) and a mean disease duration of 13.4+/-7.7 years (range 2-23). The mean time of remission in the study group was 22.2+/-5.2 months (range 11-36). Each patient was given an intravenous injection of 555MBq of 99mTc-nanocalloid (NC). Spot views of the skeleton were taken and a SPECT-CT was done on the wrists and hands. A scan was considered positive when at least one of the hand joints showed increased tracer uptake. RESULTS: The 99mTc-nanocalloid scintigraphy was negative in 14 (35%) and positive for active joint disease in 26 (65%) patients. Twenty four out of the 26 patients with positive scan (92%) were sero-positive while those who had a negative scintigraphy were all sero-negative except one. No correlation was found between the type of treatment used, the time that elapsed from remission, or laboratory parameters (ESR CRP) and the scintigraphic results. CONCLUSIONS: The clinical criteria used for remission in RA are not consistent with the actual inflammatory activity in the joints. These results are especially emphasised in the subgroup of sero-positive patients.

Prognostic significance of a prolonged international normalized ratio in elderly patients in an internal medicine ward.

PURPOSE: To investigate clinical characteristics and the prognostic significance of a prolonged international normalized ratio (INR) without obvious cause or anticoagulant treatment, in elderly inpatients. METHODS: Demographic, clinical, and laboratory data, in-hospital death and 30day-mortality were prospectively registered for 100 consecutive patients aged ≥75years admitted to an internal medicine ward for a variety of acute medical disorders, and compared according to normal (≤1.15) and prolonged (>1.15) INR on admission. Exclusion criteria were: anticoagulant therapy, disseminated intravascular coagulopathy, acute bleeding, liver disease, active malignant disorder, and known coagulopathy. RESULTS: Prolonged INR was found in 52% of patients. Patients with prolonged INR tended more likely to present with dementia and pressure sores than patients with normal INR. Moreover, patients with prolonged INR more often needed assisted feeding and presented lower mean levels of serum albumin on admission. In-hospital (21.2% vs. 6.2%) and 30-day (32.7% vs. 6.2%) mortality rates were significantly higher in patients with prolonged INR than those with normal INR. On stepwise logistic regression analysis, prolonged INR strongly predicted 30-day mortality (P=0.004, relative risk 1.67, 95% confidence interval 1.07-2.60). CONCLUSIONS: Prolonged INR without obvious cause or anticoagulant treatment is common among elderly patients admitted to an internal medicine ward, and is associated with a severe clinical profile. Prolonged INR is a powerful predictor of 30-day mortality. Assessment of INR my improve risk stratification for elderly inpatients.

Intravenous immunoglobulin and the kidney--a two-edged sword.

OBJECTIVES: To review the literature on the use and efficacy of intravenous immunoglobulin (IVIG) in glomerulonephritis and to evaluate the nephrotoxic effect of IVIG. METHODS: A structured literature search of articles published on the efficacy of IVIG in the treatment of nephritis between 1985 and 2003 was conducted. All articles dealing with lupus nephritis, IgA nephropathy, Henoch Schonlein purpura, antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis, primary membranous glomerulonephritis, and primary chronic nephritis were reviewed. The same literature search was conducted for the nephrotoxic effects of IVIG. Two groups of patients were defined: (a) a group of patients with IVIG nephrotoxic effect published as case reports, and (b) a group of patients whose data were collected by the Food and Drug Administration (FDA). All existing data of both groups were pooled and compared. RESULTS: One hundred six patients with lupus nephritis were treated with IVIG. In most reports proteinuria, nephrotic syndrome, and values of creatinine clearance were improved. In 3 cases improvement in World Health Organization (WHO) class was noted, and in 2 cases a reduction of immune deposits was demonstrated. In the other forms of autoimmune nephropathy, although the number of reported cases was small, improvement was noted in most patients. Thirty-two reports entailing 78 patients with IVIG-induced nephrotoxicity were found and their data were compared with those of 88 patients reported to the FDA. No specific differences were noted between the 2 groups of patients, as their age and indications for using IVIG were similar. Most of the patients who developed renal toxicity (72% in the literature and 90% in the FDA group) received sucrose -containing IVIG products. A high percentage of patients (31% in the literature and 40% in the FDA group) required hemodialysis. Mortality occurred in 10 and 15%, respectively. Renal histology done in a minority of the cases demonstrated vacuolization and swelling of the proximal tubules consistent with osmotic injury. CONCLUSIONS: On one hand, there are encouraging reports on the efficacy of IVIG in different types of glomerulonephritis (mainly lupus nephritis) resistant to conventional therapy, but the exact success rate and clinical indications remain undetermined. On the other hand, IVIG and the kidney is a two-edged sword, since nephrotoxicity can be a serious rare complication of IVIG therapy. Products containing sucrose as a stabilizer are mainly associated with such injury through the mechanism of osmotic nephrosis. Preexisting renal disease, volume depletion, and old age are risk factors for such toxicity.

Clinical evidence for utilization of the A3 adenosine receptor as a target to treat rheumatoid arthritis: data from a phase II clinical trial.

OBJECTIVE: Adenosine exerts antiinflammatory effects via activation of the A3 adenosine receptor (A3AR), a Gi protein-associated cell-surface receptor, overexpressed in synovial tissue and peripheral blood mononuclear cells (PBMC) in patients with active rheumatoid arthritis (RA). CF101 is a highly specific orally bioavailable A3AR agonist. METHODS: This was a multicenter study, blinded to dose, designed to assess the clinical activity and safety of CF101 in active RA. Seventy-four patients were randomized to receive 0.1, 1.0, or 4.0 mg CF101 bid for 12 weeks. The primary efficacy endpoint was American College of Rheumatology 20% response (ACR20) at Week 12. A3AR expression levels were analyzed in PBMC from 18 patients. RESULTS: . Maximal responses were observed with 1.0 mg bid, lower at 0.1 and 4.0 mg bid. At 12 weeks, 55.6%, 33.3%, and 11.5% of the patients receiving 1.0 mg CF101 achieved ACR20%, 50%, and 70% responses, respectively. CF101 was generally well tolerated, with mild headache (4.1%), nausea (2.7%), and rash (2.7%) being the most common treatment-related adverse events. Statistically significant correlations between A3AR overexpression at baseline and ACR50 and ACR70 responses were observed. CONCLUSION: CF101 administered bid for 12 weeks resulted in improvement in signs and symptoms of RA that did not achieve statistical significance, and was safe and well tolerated. The expression level of A3AR was directly correlated with patient responses to CF101, suggesting its utilization as a biomarker for the pharmacodynamic and therapeutic effects of this novel agent. These findings require confirmation in a double-blind randomized placebo-controlled trial, currently under way.

BCG immunotherapy--from pathophysiology to clinical practice.

Treatment with Bacillus Calmette-Guérin vaccine is mainly in use for superficial bladder cancer, for which it is given intravesically. Overall, this therapy is safe with only minor side effects. Arthritis secondary to such therapy has been rarely reported and usually responds well to NSAID treatment. The mechanisms leading to such a complication, as well as the clinical data, are discussed.

Neck injury and fibromyalgia-- are they really associated?

OBJECTIVE: To investigate whether whiplash injury may be a trigger for the onset of fibromyalgia (FM). METHODS: One hundred fifty-three patients presenting to the emergency room with the diagnosis of whiplash injury were examined. The control group included 53 patients hospitalized with fractures of the limbs, spine, and ribs due to road accident. The study and control groups were interviewed shortly after presenting and then followed prospectively. Patients complaining of musculoskeletal symptoms during followup were examined and a count of 18 tender points was conducted. FM was diagnosed if the patient fulfilled currently accepted 1990 American College of Rheumatology criteria. RESULTS: The mean followup period for the study and control groups was 14.5 months (range 12-18) and 9 months (range 6-14), respectively. There were no differences between the groups with regard to age, sex, marital, education, or employment status. During the followup period only one patient in the study group and no patients in the control group developed signs and symptoms of FM. Three patients in the study group (2%) and 15 patients in the control group (16%) filed insurance claims; none was associated with FM. CONCLUSION: Whiplash injury and road accident trauma were not associated with an increased rate of FM after more than 14.5 months of followup.

Methotrexate enhances the anti-inflammatory effect of CF101 via up-regulation of the A3 adenosine receptor expression.

Methotrexate (MTX) exerts an anti-inflammatory effect via its metabolite adenosine, which activates adenosine receptors. The A3 adenosine receptor (A3AR) was found to be highly expressed in inflammatory tissues and peripheral blood mononuclear cells (PBMCs) of rats with adjuvant-induced arthritis (AIA). CF101 (IB-MECA), an A3AR agonist, was previously found to inhibit the clinical and pathological manifestations of AIA. The aim of the present study was to examine the effect of MTX on A3AR expression level and the efficacy of combined treatment with CF101 and MTX in AIA rats. AIA rats were treated with MTX, CF101, or both agents combined. A3AR mRNA, protein expression and exhibition were tested in paw and PBMC extracts from AIA rats utilizing immunohistochemistry staining, RT-PCR and Western blot analysis. A3AR level was tested in PBMC extracts from patients chronically treated with MTX and healthy individuals. The effect of CF101, MTX and combined treatment on A3AR expression level was also tested in PHA-stimulated PBMCs from healthy individuals and from MTX-treated patients with rheumatoid arthritis (RA). Combined treatment with CF101 and MTX resulted in an additive anti-inflammatory effect in AIA rats. MTX induced A2AAR and A3AR over-expression in paw cells from treated animals. Moreover, increased A3AR expression level was detected in PBMCs from MTX-treated RA patients compared with cells from healthy individuals. MTX also increased the protein expression level of PHA-stimulated PBMCs from healthy individuals. The increase in A3AR level was counteracted in vitro by adenosine deaminase and mimicked in vivo by dipyridamole, demonstrating that receptor over-expression was mediated by adenosine. In conclusion, the data presented here indicate that MTX induces increased A3AR expression and exhibition, thereby potentiating the inhibitory effect of CF101 and supporting combined use of these drugs to treat RA.