Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What Have We Learned?

The use of different pathways in the treatment of rheumatoid arthritis has led to a significant decrease in the number of treatment-resistant patients. In this context, interleukin (IL)-6 inhibition has filled an important gap in rheumatoid arthritis treatment with its effectiveness and safety in both monotherapy and combinations. The process of IL-6 inhibition initiated with IL-6 receptor blockers has prompted questions regarding the potential impact and safety of different inhibitions of this pathway, such as the direct blockade of IL-6. Following the termination of the development of sirukumab because of mortality data in early studies, the investigation of olokizumab, which targets a different region of the IL-6 cytokine, has renewed the hope in this area and the safety concerns have been largely alleviated by the open-label extension data. In addition, the efficacy and safety of tocilizumab and sarilumab have led to a rapid investigation of biosimilars and new potent IL-6 receptor blockers. A comprehensive understanding of mechanisms of this pathway with further long-term clinical data and basic research may provide a decisive impact on selecting the appropriate mechanism as the first choice in personalized treatments.

The role of upadacitinib in the treatment of moderate-to-severe active rheumatoid arthritis.

Despite recent promising developments in the treatment of rheumatoid arthritis (RA), a substantial proportion of patients still cannot achieve the treatment targets: low disease activity and remission. Janus kinase (JAK) inhibitors have the potential to fill this important gap with their high efficiency, rapid onset of action, and acceptable safety profile. The fact that the previously approved two JAK inhibitors, tofacitinib and baricitinib, inhibit more than one JAK molecule raised the question whether a safer profile can be possible by inhibiting fewer JAK molecules. Upadacitinib, a JAK 1 selective molecule developed in this context has been evaluated in the SELECT phase-III study program and demonstrated a high and rapid efficacy in monotherapy as well as in combination with csDMARDs both in csDMARD-naive RA patients and in patients refractory to csDMARD and bDMARD treatments. Upadacitinib 15 mg once daily displayed a similar safety profile except for increased creatine phosphokinase (CPK) levels and herpes zoster (HZ) risk compared to its active comparators methotrexate (MTX) and adalimumab. Most of the CPK elevations were asymptomatic, and most of the HZ cases were not serious. Along with the randomized-controlled studies and meta-analysis results, upadacitinib 15 mg once daily has a favorable efficacy/safety profile. Long-term extensions of current studies and real-world data will be important to fully appreciate its potential in the treatment of RA.

Early phase studies of JAK1 selective inhibitors in rheumatoid arthritis.

The first approved Janus kinase (JAK) inhibitors for treatment of RA targeted more than one JAK molecule. Although this brings an advantage of simultaneous blocking of more cytokines involved in RA, it may also carry an increased risk of toxicity. Subsequently, more selective JAK inhibitors were developed with the aim of improving the safety-efficacy profile and to further increase drug maintenance. With this proposal, early phase trials of selective JAK1 inhibitors, namely upadacitinib, filgotinib and itacitinib, were initiated in recent years to identify the efficacy and adverse effects of these agents and to define their potential role in treatment of inflammatory and autoimmune diseases. Early phase (Phase I-II) studies of upadacitinib and filgotinib provided evidence for efficacy and safety of the selective JAK1 inhibitors in refractory populations of RA patients and allowed informed selection of the appropriate dose by balancing the optimal benefit-risk profile for further evaluation in the later successfully performed Phase III trials. Although itacitinib also demonstrated a good efficacy and safety in a Phase II trial in RA patients, it is mainly in development for haematologic and oncologic conditions.

Targeting IL-6 or IL-6 Receptor in Rheumatoid Arthritis: What's the Difference?

Interleukin-6 (IL-6) signaling is a critical target in inflammatory pathways. Today, tocilizumab (TCZ) and sarilumab (SAR), two IL-6 receptor-inhibiting monoclonal antibodies, are widely used in the treatment of rheumatoid arthritis (RA), with a favorable efficacy/safety profile. Successful introduction of such agents in the treatment of RA has encouraged the development of other agents targeting different points of the pathway. Sirukumab (SRK), a human anti-IL-6 monoclonal antibody, has been evaluated in clinical trials and showed largely similar clinical efficacy compared with TCZ and other IL-6 pathway-targeting agents. Furthermore, the drug safety profile seemed to reflect the profile of adverse effects and laboratory abnormalities seen in other inhibitors of the IL-6 pathway. However, increased death rates under SRK treatment compared with placebo raised safety concerns, which led to the decision by the FDA to decline the approval of SRK in August 2017. However, during the 18-week true placebo-controlled period, mortality rates were identical in the placebo- and SRK-treated patients. Comparisons after week 18 may be confounded by some factors, and also the 'crossover' design resulted in various treatment groups with varying drug exposure periods. The limited placebo exposure relative to SRK exposure makes interpretation of mortality rates difficult. We do not know whether the imbalance in mortality rates seen for SRK is a true safety signal or a result of bias due to the study design. Therefore, further long-term clinical data as well as basic research is needed to allow deeper insight into IL-6 signaling.

Targeting GM-CSF in rheumatoid arthritis.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is well-known as a haemopoietic growth factor. However, it is also essential in regulating functions of mature myeloid cells such as macrophages. Preclinical studies and observations of flares of arthritis in patients following GM-CSF treatment supported its important contribution to the pathogenesis of rheumatoid arthritis (RA). As the most advanced compound, mavrilimumab, a monoclonal antibody against GM-CSF receptor, has already completed phase II trials with a long term of follow-up period of 74 weeks. During this exposure period, an acceptable sustained safety and tolerability profile has been observed addressing the concerns of development of cytopenias or pulmonary alveolar proteinosis. Of note, a rapid and sustained efficacy and normalisation of acute phase reactants were consistently shown in studies both targeting GM-CSF and its receptor. Its tumour necrosis factor (TNF) independent mode of action with concurrent blockade of GM-CSF as well as IL-17 signalling reported from preclinical studies supports the assumption that it can be a useful biologic and an alternative agent in TNF inhibitor resistant patients with RA. Therefore, subsequent studies are warranted to investigate the safety and efficacy of GM-CSF blocking agents in different subgroups of RA.

Characteristics Predicting Tuberculosis Risk under Tumor Necrosis Factor-α Inhibitors: Report from a Large Multicenter Cohort with High Background Prevalence.

OBJECTIVE: Screening strategies for latent tuberculosis (TB) before starting tumor necrosis factor (TNF)-α inhibitors have decreased the prevalence of TB among patients who are treated with these agents. However, despite vigilant screening, TB continues to be an important problem, especially in parts of the world with a high background TB prevalence. The aim of this study was to determine the factors related to TB among a large multicenter cohort of patients who were treated with anti-TNF. METHODS: Fifteen rheumatology centers participated in this study. Among the 10,434 patients who were treated with anti-TNF between September 2002 and September 2012, 73 (0.69%) had developed TB. We described the demographic features and disease characteristics of these 73 patients and compared them to 7695 patients who were treated with anti-TNF, did not develop TB, and had complete data available. RESULTS: Among the 73 patients diagnosed with TB (39 men, 34 women, mean age 43.6 ± 13 yrs), the most frequent diagnoses were ankylosing spondylitis (n = 38) and rheumatoid arthritis (n = 25). More than half of the patients had extrapulmonary TB (39/73, 53%). Six patients died (8.2%). In the logistic regression model, types of anti-TNF drugs [infliximab (IFX), OR 3.4, 95% CI 1.88-6.10, p = 0.001] and insufficient and irregular isoniazid use (< 9 mos; OR 3.15, 95% CI 1.43-6.9, p = 0.004) were independent predictors of TB development. CONCLUSION: Our results suggest that TB is an important complication of anti-TNF therapies in Turkey. TB chemoprophylaxis less than 9 months and the use of IFX therapy were independent risk factors for TB development.

Biologicals in rheumatoid arthritis: current and future.

The aim of the review is to highlight the current knowledge about established and new biologicals and to summarise recent advances by focusing on comparative efficacy, safety and possible discontinuation of treatment in patients with rheumatoid arthritis (RA). Up to now, comparative analyses showed only minor differences with respect to efficacy and safety among the established biologicals. Studies confirmed the excellent drug retention rate as well as efficacy and safety of approved biologicals including their use in monotherapy. Tapering and in some instances discontinuation of biologicals is possible in disease remission. In case of relapse, patients usually show full response after reintroduction of the same compound. The development of biologicals continues fast with several new biologicals targeting different or established cytokines or cellular subsets of the immune system. With several new biologicals in the pipeline and different formulations for established compounds, treatment options for RA will become even more versatile and sophisticated. Although we get closer to the aim of decreasing the proportion of refractory patients, many questions have to be addressed in the near future regarding emerging biosimilars and biologicals with new modes of action.

The rate and significance of type 1/type 2 serum amyloid A protein gene polymorphisms in patients with ankylosing spondylitis and amyloidosis.

A relationship between the presence of amyloidosis and SAA1 genotype has been shown in recent studies of (principally) familial Mediterranean fever patients. We found that the SAA1 rs12218 polymorphism was significantly more prevalent in ankylosing spondylitis patients with amyloidosis.

Significant Association between Serum Levels of Von Willebrand Factor (vWF) Antigen with Stages of Cirrhosis.

OBJECTIVE: Von Willebrand factor (vWF) is a mediator that increases endotoxemic medium like in cirrhosis. In this study we evaluated the association of serum VWF antigen (Ag) level with the stage of cirrhosis (according to Child-Pugh classification). MATERIALS AND METHODS: We included 82 cirrhotic patients (Female/Male (F/M): 26/56) and 86 healthy subjects (F/M: 44/42) in the study. Ages of the both groups of patients were not different (P= 0.095). We excluded possible other reasons that may cause VWF level increase. Diagnosis of cirrhosis was made on the basis of biopsy in 7 patients and with clinical and laboratory parameters in 75 patients. VWF Ag level was determined by immunoturbidimetric test. The stage of cirrhosis was defined with Child-Pugh classification. Data were analysed by using Statistical Package for the Social Sciences (SPSS) 10.0 software program. RESULTS: VWF Ag level was significantly higher in cirrhotic patients compared to control group (220±90 and 87±38, P<0.001, respectively). We observed significant increase of VWF Ag level with the increasing stages of cirrhosis according to Child-Pugh score (VWF Ag level for Child A-B-C 156.4±54/215±45/284.8±93, respectively; P values for Child A-B/A-C/B-C; <0.001/<0.001/0.006, respectively). CONCLUSION: Serum VWF Ag level increases in cirrhotic patients and this is more pronounced with higher stages of cirrhosis.

Acute renal failure due to uterine prolapse: a case report.

Herein, we present a successfully treated case with acute renal failure due to ureteral obstruction caused by total uterine prolapsed. A 55-year-old female patient presented to our hospital with the complaints of protrusion of the uterus for the last 3 months, pollakiuria, nocturia, decreased urine volume, and swelling of her body for the last week, and as well as impaired general status with shortness of breath for the last several days. Her physical examination revealed a blood pressure of 140/90 mmHg, pulse rate of 80 beats/min, body temperature of 37.8 °C, as well as uterine prolapse with infection and erosion on the surface of the uterus, crepitating rales in the basal segments of both lungs, and pretibial edema. Results of laboratory analyses were as follows: BUN = 70 mg/dL, Cr = 6.5 mg/dL, CRP = 8.7 mg/dL, and leukocyte = 12,000/mm(3). Blood gas analysis revealed a pH of 7.35 and bicarbonate level of 14 mmol/L. Data obtained from ultrasonography, DTPA scintigraphy, and abdominal CT, which were performed assuming that the patient had post-renal renal failure due to the compression by uterus, supported this assumption. Bilateral nephrostomy catheters were inserted and appropriate fluid-electrolyte therapy for volume status and antibiotherapy were commenced. Renal functions returned to normal levels on the 4th day of therapy and her complaints disappeared. The patient underwent total abdominal hysterectomy and was monitored in terms of renal functions and diuresis. The present case was presented due to its importance for being a quite rare case who dramatically responded to accurate intervention performed in time.

Relationship of increased serum brain natriuretic peptide levels with hepatic failure, portal hypertension and treatment in patients with cirrhosis.

BACKGROUND/AIMS: Brain natriuretic peptide is a cardiac neurohormone secreted from ventricles in response to end diastolic pressure and increased volume. It has diuretic, natriuretic and vasodilator effects. In cirrhosis, a hyperdynamic circulation occurs because of hemodynamic and hemostatic alterations. The increase in brain natriuretic peptide concentration shows parallelism with the stage of cirrhosis. The aim of this study is to investigate the relation of increased brain natriuretic peptide level with the pathophysiologic components of cirrhosis and treatment. METHODS: Ninety-five cirrhotic patients in different stages (Child-A: 33; Child-B: 25; Child-C:37) and age and sex matched 86 healthy individuals were recruited for the study. Brain natriuretic peptide concentration was measured with brain natriuretic peptide-Triage test device using fluoresan immune assay method. RESULTS: Brain natriuretic peptide levels of patients with hepatic cirrhosis were significantly higher compared to control group (288.5±329.2/60.2±29.5/p=0.000, respectively). Serum brain natriuretic peptide levels were positively correlated with Child score (Child A-B-C; 201.2±266/258.7±233.6/386.5±407.7, respectively). A negative correlation was observed between brain natriuretic peptide and albumin levels (p=0.002). Brain natriuretic peptide concentration was significantly correlated with the grade of esophagus varices, and presence of ascites and collateral circulation (p=0.006; p=0.001; p=0.002; respectively). Patients receiving with beta-blocker and diuretic treatments had significantly higher brain natriuretic peptide levels. CONCLUSIONS: High brain natriuretic peptide levels in patients with cirrhosis may be due to hepatocellular insufficiency or portal hypertension, but a cardiomyopathy developing insiduously should not be regarded.

Lung involvement in patients with primary Sjögren's syndrome: what are the predictors?

The aim of this study was to investigate the prevalence, predictors and radiological findings of primary Sjögren's syndrome (pSS)-associated lung involvement. This retrospective cohort study included 123 patients with demographic, clinical, laboratory and radiological data who were diagnosed with pSS. Lung involvement was defined based on the presence of pulmonary signs/symptoms and/or impaired pulmonary function tests along with alterations in high-resolution computerized tomography (HRCT). Thirty patients (24.4%) had pulmonary signs/symptoms at the initial presentation and/or during the follow-up period. Based on the criteria, 14 patients (11.4%) were defined as having pSS with lung involvement. The smoking rate, male/female ratio and the mean ages were found to be higher in patients with lung involvement (P < 0.05). Positive IgM-rheumatoid factor (RF), anti-La and anti-Ro results, the presence of hypergammaglobulinemia and lymphopenia had high specificity despite the low sensitivity rates to detect pSS-associated lung disease. A significant difference was found in forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV(1)) results between the patients with and without lung involvement. Impaired FEV(1) had high specificity and positive predictive value compared to impaired FVC, particularly in non-smoker patients. The most frequent HRCT finding was ground-glass attenuation (64.3%). Other common findings were bronchiectasis, reticular pattern and honeycombing. The lesions involved predominantly the lower lobes. In conclusion, the presence of hypergammaglobulinemia and lymphopenia, positivity for RF, anti-La and anti-Ro, and impaired (FVC) and/or FEV(1) values could be the predictive parameters with a high specificity despite the low sensitivity rates. Smoking history, male gender and age are also risk factors. These parameters may be helpful to distinguish pSS-associated lung involvement from lung disorders unrelated to pSS.

A case of primary Sjögren's syndrome with pulmonary-limited Wegener's granulomatosis.

A 60-year-old woman had a history of dyspnea for 5-6 weeks. The chest radiograph and computed tomography scans revealed bilateral patchy reticulonodular pattern. The patient had positive test results for antineutrophil cytoplasmic antibody against proteinase-3 (c-ANCA), antinuclear antibody and anti-Ro antibody. According to European Study Group on Classification Criteria for Sjögren's Syndrome, the patient was diagnosed as primary Sjögren's syndrome based on the presence of clinical features, positive findings on Schirmer's test and parotis scintigraphy. Lung biopsy obtained by wedge resection showed granulomatous inflammation with extensive multinuclear giant cells involving the lung parenchyma and vascular structures. There was neither upper airway nor renal involvement. Thus, the patient was simultaneously diagnosed as pulmonary-limited Wegener's granulomatosis. With this unique case, we would like to emphasize that the awareness of ANCA-associated vasculitis as a diagnostic possibility in primary Sjögren's syndrome is important during the work-up of lung lesions.

Diagnostic performance of minor salivary gland biopsy, serological and clinical data in Sjögren's syndrome: a retrospective analysis.

The aim of this study was to investigate the performance of minor salivary gland biopsy (MSGB), serological and clinical data in diagnosis of primary Sjögren's syndrome (pSS). Retrospective review of 216 patients who underwent minor labial salivary gland biopsy in last 5 years was performed. Results of the patients with diagnosis of pSS were compared with the patients failing to fill the classification criteria of pSS. Two groups did not differ significantly in terms of clinical symptoms and signs except presence of Raynaud's phenomenon. Specificity and positive likelihood ratio of clinical signs in diagnosis of pSS were quiet low. A total of 78.7% of pSS patients had a focus score >or=1 (Chiscolm's score III/IV) while all of the non-SS patients had a focus score <1 (P < 0.001). MSGB has the best predictive value with highest sensitivity and specificity for pSS diagnosis. Serological markers have higher predictive values compared to clinical symptoms and signs. Presence of Raynaud's phenomenon, lymphopenia and/or hypergammaglobulinemia strengthens the probability of pSS in a patient with sicca symptoms.

Pain perception of patients predisposed to anxiety and depressive disorders in emergency department.

The aim of this study was to reveal the effects of anxiety and depression on pain perception in the emergency setting. This randomized prospective study was performed in an urban tertiary care hospital emergency department (ED). Consecutive patients presenting to the ED with pain who had an intramuscular injection of diclofenac sodium were enrolled in the study. The prevalence of anxiety and depressive disorders in study subjects was determined by using the Hospital Anxiety and Depression Scale. A total of 302 patients were included. Study subjects had a mean age of 41.3 +/- 13.7 years and 35.4% (n = 107) were male. Pain perception in women was significantly higher than in men (median 8.5 vs. 5, respectively; p = .033). Pain perception in elderly patients, >/=65 years old, was found to be lower than in patients <65 years old (median 1 vs. 6.5, respectively; p = .02). Anxiety was found to be related to higher pain perception after adjusting for confounding variables (13.8 vs. 7.6, respectively; adjusted p = .022). Gender, age, and anxiety, but not depression, are possible factors related to pain perception in the emergency setting. Further studies are needed to reveal the factors affecting pain perception and the complex relationship between psychiatric status and pain.

Comparison of systemic and local effects of nitric acid and hydrochloric acid: an experimental study in a rat model.

BACKGROUND: We aimed to determine the local and systemic effects of widely available household cleaners, namely 45% nitric acid (NHO(3)), and 18% hydrochloric acid (HCl), in a rat model. METHODS: This prospective, experimental, placebo-controlled trial was carried out in the Animal Research Laboratory of Akdeniz University hospital. Commonly available solution of 45% NHO(3) and 18% HCl were tested against normal saline. Each solution was administrated orally to groups consisting of ten rats. The metabolic changes were determined by measuring the pH and calcium (Ca) levels before and after the administration of solutions. In addition, the pathological changes and mortality rates were determined for each group. RESULTS: There was a statistically significant increase in the post-ingestion (30 minutes later) Ca levels and a decrease in the post-ingestion pH levels after the administration of test solution in the NHO(3) (p=0.006 for Ca increase, p=0.001 for pH decrease) and HCl (p=0.007 for Ca increase, p=0.023 for pH decrease) groups. There was also a statistically significant difference between groups for Ca increase (p=0.000) and pH decrease (p=0.006). In post hoc analysis, the difference between the groups was found to be originated from the placebo group. In the pathological evaluation of esophagus and stomach, there was a statistically significant difference between groups (p=0.009 (E) and p=0.016 (S)) and the difference was found to be originated from the control group (p=0.543 (E), p=0.244 (S) for NHO(3) and HCl). The 30-minute mortality rates were 0,2 in the NHO(3) group, 0,6 in the HCl group and 0 in the control group. CONCLUSION: Serious metabolic and mild local pathological changes can occur after the ingestion of household NHO3 and HCl solutions. Further studies should be performed to elucidate the causes of death following oral ingestion of these compounds and appropriate public health warnings should be taken.