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ID PMID Title PublicationDate abstract
25606593 Current and emerging therapeutic strategies for preventing inflammation and aggrecanase-me 2014 Arthritis is a multifactorial disease for which current therapeutic intervention with high efficacy remains challenging. Arthritis predominately affects articular joints, and cartilage deterioration and inflammation are key characteristics. Current therapeutics targeting inflammatory responses often cause severe side effects in patients because of the systemic inhibition of cytokines or other global immunosuppressive activities. Furthermore, a lack of primary response or failure to sustain a response to treatment through acquired drug resistance is an ongoing concern. Nevertheless, treatments such as disease-modifying anti-rheumatic drugs, biological agents, and corticosteroids have revealed promising outcomes by decreasing pain and inflammation in patients and in some cases reducing radiographic progression of the disease. Emerging and anecdotal therapeutics with anti-inflammatory activity, alongside specific inhibitors of the A Disintegrin-like And Metalloproteinase domain with Thrombospondin-1 repeats (ADAMTS) cartilage-degrading aggrecanases, provide promising additions to current arthritis treatment strategies. Thus, it is paramount that treatment strategies be optimized to increase efficacy, reduce debilitating side effects, and improve the quality of life of patients with arthritis. Here, we review the current strategies that attempt to slow or halt the progression of osteoarthritis and rheumatoid arthritis, providing an up-to-date summary of pharmaceutical treatment strategies and side effects. Importantly, we highlight their potential to indirectly regulate ADAMTS aggrecanase activity through their targeting of inflammatory mediators, thus providing insight into a mechanism by which they might inhibit cartilage destruction to slow or halt radiographic progression of the disease. We also contrast these with anecdotal or experimental administration of statins that could equally regulate ADAMTS aggrecanase activity and are available to arthritis sufferers worldwide. Finally, we review the current literature regarding the development of synthetic inhibitors directed toward the aggrecanases ADAMTS4 and ADAMTS5, a strategy that might directly inhibit cartilage destruction and restore joint function in both rheumatoid arthritis and osteoarthritis.
23727635 Antibodies from patients with rheumatoid arthritis target citrullinated histone 4 containe 2014 Jul BACKGROUND: Histone deimination regulates gene function and contributes to antimicrobial response, allowing the formation of neutrophil extracellular traps (NETs). Deiminated proteins are target of anti-citrullinated peptides antibodies (ACPA) in rheumatoid arthritis (RA). OBJECTIVE: The objective of this paper is to test the hypothesis that RA sera react with deiminated histones contained in NETs. METHODS: Neutrophils from peripheral blood were stimulated with A23187 and acid treated; NETosis was induced by phorbol myristate acetate, and NET proteins were isolated. Sera were tested by immunoblot on acid extracted proteins from neutrophils and from NETs, and by ELISA on deiminated histone H4 or H4-derived peptides. Bands reactive with RA sera were excised from gels, digested with trypsin and subjected to matrix-assisted laser desorption/ionisation time of flight (MALDI-TOF) analysis, before and after derivatisation to detect citrullinated peptides. RESULTS: RA sera reacted with a deiminated antigen of 11 KDa from activated neutrophils, recognised also by anti-H4 and antideiminated H4 antibodies. A similar reactivity was observed with NET proteins. The antigen from neutrophils or NETs was identified as citrullinated H4 by MALDI-TOF analysis. By ELISA, RA sera bound in vitro citrullinated H4. Citrullinated H4 14-34 and 31-50 peptides detected antibodies in 67% and 63% of RA sera and in less than 5% of controls; antibody titre was correlated with anti-CCP2. CONCLUSIONS: Citrullinated H4 from activated neutrophils and NETs is a target of antibodies in RA, and synthetic citrullinated H4-derived peptides are a new substrate for ACPA detection. As NETosis can generate antigens for ACPA, these data suggest a novel connection between innate and adaptive immunity in RA.
24241152 The histone deacetylase inhibitors MS-275 and SAHA suppress the p38 mitogen-activated prot 2013 Nov 14 MS-275 (entinostat) and SAHA (vorinostat), two histone deacetylase (HDAC) inhibitors currently in oncological trials, have displayed potent anti-rheumatic activities in rodent models of rheumatoid arthritis (RA). To further elucidate their anti-inflammatory mechanisms, the impact of MS-275 and SAHA on the p38 mitogen-activated protein kinase (MAPK) signaling pathway and chemotaxis was assessed in human rheumatoid arthritic synovial fibroblastic E11 cells. MS-275 and SAHA significantly suppressed the expression of p38α  MAPK, but induced the expression of MAPK phosphatase-1 (MKP-1), an endogenous suppressor of p38α  in E11 cells. At the same time, the association between p38α and MKP-1 was up-regulated and consequently, the activation (phosphorylation) of p38α  was inhibited. Moreover, MS-275 and SAHA suppressed granulocyte chemotactic protein-2 (GCP-2), monocyte chemotactic protein-2 (MCP-2) and macrophage migration inhibitory factor (MIF) in E11 cells in a concentration-dependent manner. Subsequently, E11-driven migration of THP-1 and U937 monocytes was inhibited. In summary, suppression of the p38 MAPK signaling pathway and chemotaxis appear to be important anti-rheumatic mechanisms of action of these HDAC inhibitors.
23370945 Large B cell lymphoma of the subtalar and talonavicular joint synovium. 2013 Jan 30 We present the unique case of a 68-year-old man with a background of rheumatoid arthritis, who underwent left subtalar and talonavicular arthrodesis due to degenerative changes and chronic pain. Histology of the synovium demonstrated large B cell lymphoma. The patient subsequently underwent R-CHOP chemotherapy and radiotherapy to the affected area. This is the first described case of a primary large B cell lymphoma of the subtalar and talonavicular joints, without bony involvement.
23312539 Rheumatoid arthritis patients with xerostomia have reduced production of key salivary cons 2013 Apr OBJECTIVE: The aim of this study was to assess the relationship between complaints of xerostomia in patients with rheumatoid arthritis (RA) with the total output of the salivary proteins of innate and adaptive immunity. STUDY DESIGN: The salivary output and specific activity of peroxidase and specific contents of lysozyme, lactoferrin, and secretory immunoglobulin A (sIgA) were determined in xerostomic RA patients, nonxerostomic RA patients, and healthy control subjects. RESULTS: Compared with nonxerostomic RA and healthy control groups, xerostomic RA patients had significantly decreased output of saliva and protein, decreased peroxidase activity, and a significantly lower specific content of peroxidase and sIgA. Compared with the RA control group, xerostomic RA patients had significantly lower specific content of all salivary proteins examined. CONCLUSIONS: The results indicate that xerostomia in patients with RA may be a harbinger of diminished saliva production regarding quantity and quality, and may be indicative of impairment of the salivary immune system of the oral cavity in xerostomic RA patients.
22749663 Similarities and differences in fluorodeoxyglucose positron emission tomography/computed t 2013 Mar OBJECTIVES: We assessed fluorine-18 ((18)F)-labelled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) findings in patients with seronegative spondyloarthritis (SpA), polymyalgia rheumatica (PMR), and rheumatoid arthritis (RA). METHODS: We studied 53 patients with SpA (n=21), PMR (n=16), or RA (n=16) admitted to our hospital between 2006 and 2011. Disease activity in the ischial tuberosities, greater trochanters, spinous processes, vertebral bodies, and sacroiliac joints (SIJ) were evaluated by determining FDG accumulation using maximum standardized uptake values (SUV(max)) and FDG scores. RESULTS: SUV(max) for ischial tuberosities was significantly higher in PMR than SpA or RA. SUV(max) for greater trochanters and spinous processes was significantly higher in PMR than RA (P<0.001) and significantly higher in SpA than in PMR or RA for SIJ (P=0.01). No significant difference in vertebral scores was observed among groups (P=0.488). FDG scores yielded similar results. X-ray findings were consistent with PET/CT findings in 3/15 (20%) patients with sacroiliitis, whereas magnetic resonance imaging findings were consistent with PET/CT findings in 4/7 (57.1%) patients. CONCLUSIONS: PET/CT detection of inflammation in the ischial tuberosities, greater trochanters, and spinous processes discriminated between PMR and RA, but not between SpA and PMR. PET/CT findings can distinguish SpA from RA and PMR and are useful for the early diagnosis of sacroiliitis.
23623037 Targeting the complement system in systemic lupus erythematosus and other diseases. 2013 Sep The importance of the complement system in the pathogenesis of systemic lupus erythematosus (SLE) has long been recognized. However, despite an unprecedented amount of SLE clinical trial activities ongoing at this time, complement inhibitors have been omitted from the therapeutic assault on this disease. We review data generated from murine lupus that provide scientific support for the study of human SLE. Also reviewed is the sole study of a complement inhibitor, eculizumab, performed in patients with SLE. We conclude with a review of other inflammatory diseases where ongoing programs might provide the groundwork for the development of complement inhibitors in SLE.
24663106 Non-steroidal anti inflammatory drugs, glucocorticoids and disease modifying anti-rheumati 2014 May PURPOSE OF REVIEW: To review the recent literature on the safety of nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids and traditional disease-modifying antirheumatic drugs before and during pregnancy. RECENT FINDINGS: Recent data suggest that the risk of cleft palate formation after in-utero glucocorticoid exposure is lower than previously reported. Two studies of inadvertent leflunomide exposure during early pregnancy suggest that this medication may be less teratogenic than previously thought. SUMMARY: Although NSAIDs are well tolerated for use during the first two trimesters of pregnancy, they should be avoided during a conception cycle so as not to impede implantation. After gestational week 30, these medications should be discontinued as they may cause premature closure of the ductus arteriosus. The nonfluorinated glucocorticoids, prednisone and prednisolone, can be used throughout pregnancy, although use during the first trimester may increase the risk of cleft palate formation. Protracted glucocorticoids exposure during pregnancy can cause maternal preterm premature rupture of the membranes, gestational hypertension and gestational diabetes. Methotrexate and leflunomide are teratogenic and should be avoided during pregnancy. The immunosuppressive agents, azathioprine, 6-mercaptopurine and cyclosporine A, are compatible with pregnancy.
23487172 Antigen microarrays for the study of autoimmune diseases. 2013 Jul BACKGROUND: The immune response involves the activation of heterogeneous populations of T cells and B cells that show different degrees of affinity and specificity for target antigens. Although several techniques have been developed to study the molecular pathways that control immunity, there is a need for high-throughput assays to monitor the specificity of the immune response. CONTENT: Antigen microarrays provide a new tool to study the immune response. We reviewed the literature on antigen microarrays and their advantages and limitations, and we evaluated their use for the study of autoimmune diseases. Antigen arrays have been successfully used for several purposes in the investigation of autoimmune disorders: for disease diagnosis, to monitor disease progression and response to therapy, to discover mechanisms of pathogenesis, and to tailor antigen-specific therapies to the autoimmune response of individual patients. In this review we discuss the use of antigen microarrays for the study of 4 common autoimmune diseases and their animal models: type 1 diabetes, systemic lupus erythematosus, rheumatoid arthritis, and multiple sclerosis. CONCLUSIONS: Antigen microarrays constitute a new tool for the investigation of the immune response in autoimmune disorders and also in other conditions such as tumors and allergies. Once current limitations are overcome, antigen microarrays have the potential to revolutionize the investigation and management of autoimmune diseases.
24886976 Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy 2014 May 22 INTRODUCTION: Regulatory T (Treg) cells play a crucial role in preventing autoimmune diseases and are an ideal target for the development of therapies designed to suppress inflammation in an antigen-specific manner. Type 1 regulatory T (Tr1) cells are defined by their capacity to produce high levels of interleukin 10 (IL-10), which contributes to their ability to suppress pathological immune responses in several settings. The aim of this study was to evaluate the therapeutic potential of collagen type II-specific Tr1 (Col-Treg) cells in two models of rheumatoid arthritis (RA) in mice. METHODS: Col-Treg clones were isolated and expanded from collagen-specific TCR transgenic mice. Their cytokine secretion profile and phenotype characterization were studied. The therapeutic potential of Col-Treg cells was evaluated after adoptive transfer in collagen-antibody- and collagen-induced arthritis models. The in vivo suppressive mechanism of Col-Treg clones on effector T-cell proliferation was also investigated. RESULTS: Col-Treg clones are characterized by their specific cytokine profile (IL-10(high)IL-4(neg)IFN-γ(int)) and mediate contact-independent immune suppression. They also share with natural Tregs high expression of GITR, CD39 and granzyme B. A single infusion of Col-Treg cells reduced the incidence and clinical symptoms of arthritis in both preventive and curative settings, with a significant impact on collagen type II antibodies. Importantly, injection of antigen-specific Tr1 cells decreased the proliferation of antigen-specific effector T cells in vivo significantly. CONCLUSIONS: Our results demonstrate the therapeutic potential of Col-Treg cells in two models of RA, providing evidence that Col-Treg could be an efficient cell-based therapy for RA patients whose disease is refractory to current treatments.
24057090 Comparison of tuberculosis incidence in ankylosing spondylitis and rheumatoid arthritis du 2014 Sep Clinical characteristics of antitumor necrosis factor (TNF) agents-related tuberculosis (TB) in ankylosing spondylitis (AS) are not well described. The aim was to compare the incidences and the characteristics of TB in AS and rheumatoid arthritis (RA) during TNF inhibitor treatment. AS (n = 1,322) and RA (n = 3,154) patients who received medical care between January 2001 and August 2011 were enrolled. The incidence of TB in patients treated, or not, with TNF inhibitors and the clinical features associated with TB were explored. Seven patients with AS and seven with RA developed TB while receiving TNF inhibitor therapy, resulting in an incidence rate of 600.2/100,000 person-years (PYs) (95 % confidence interval (CI), 241.3-1236.3) for those with AS and 771.6/100,000 PYs (95 % CI, 310.2-1589.9) for those with RA. Incidence rate ratios for TNF inhibitor-treated vs. untreated patients were 4.87 for AS (95 % CI, 1.50-15.39; p < 0.001) and 3.61 for RA (95 % CI, 1.38-8.07; p < 0.001). Low body mass index was identified as a significant risk factor for TB in the AS group (odds ratio (OR), 13.0; p = 0.002). Extrapulmonary TB was predominant at 85.7 % during TNF inhibitor treatment. Three (42.8 %) of the AS patients, but none of the RA patients, developed TB with concomitant isoniazid. All AS patients recovered from TB whereas two of seven RA patients died. Treatment with TNF inhibitors significantly increases the risk of extrapulmonary TB in AS. Symptoms of infection should warrant clinicians to evaluate for TB during TNF inhibitor therapy in AS patients.
25199003 LTBI screening in rheumatoid arthritis patients prior to anti-TNF treatment in an endemic 2014 Aug SETTING: Recommendations for screening for latent tuberculous infection (LTBI) in patients eligible for anti-tumour necrosis factor (TNF) agents remain unclear in endemic regions. OBJECTIVE: To evaluate the long-term efficacy of LTBI screening and treatment in patients with rheumatoid arthritis (RA) receiving TNF blockers. DESIGN: A total of 202 RA patients were screened for LTBI before receiving anti-TNF treatment using the tuberculin skin test (TST), chest X-ray (CXR) and history of exposure to tuberculosis (TB). All subjects were regularly followed at 1- to 3-month intervals. RESULTS: Eighty-five patients (42%) were treated with a single anti-TNF agent, while 117 patients (58%) changed anti-TNF agents once or twice. LTBI screening was positive in 66 patients, 44 were TST-positive, 23 had a history of TB exposure and 14 had an abnormal CXR. Exposure alone accounted for LTBI diagnosis in 14 patients with a negative TST. LTBI patients were treated with isoniazid (300 mg/day) for 6 months, and none developed TB. During follow-up, TST was repeated in 51 patients. Conversion was observed in 5; 3 were diagnosed with LTBI and 2 with active TB respectively 14 and 36 months after receiving anti-TNF treatment, suggesting new TB exposure. CONCLUSION: LTBI screening and treatment before anti-TNF treatment is effective in endemic areas and reinforces the importance of establishing contact history for diagnosing LTBI in RA patients.
24637471 Anti-TNF-α and risk of infections: the experience in one center. 2014 Mar AIM: In the last years there is an increasing interest for the question of whether patients treated with antitumour necrosis factor-α (TNF-α) agents are at increased risk of infections. We aim to assess the possible role of anti-TNF-α treatment in the increase of the risk of infections in a population of patients affected by rheumatoid arthritis or psoriatic arthritis. METHODS: We analyzed data of patients affected by chronic arthritis treated with anti-TNF-α to investigate the risk of infections. Statistical analysis was done using STATA software. RESULTS: The odds ratio for patients treated with anti-TNF-α who developed infections was 1.61 (CI: 0.88, 2.92, P<0.11). We found an odds ratio of 1.41 (CI: 0.74, 2.68, P<0.29) in patients treated with anti-TNF-α who developed urinary tract infection, and an odds ratio of 2.63 (CI: 0.31, 22.19, P<0.37) in patients treated with anti-TNF-α who developed herpes zoster. DISCUSSION: These results seems to indicate a role of anti-TNF-α treatment in the risk of infection. Nevertheless, our results are not statistically significant probably because the sample sizes are too small and the time of observation among patients is variable. Moreover, other confounding factors may be gender, age and the different degrees of disease activity and comorbidity. In conclusion, limitations in the study size and design preclude definitive conclusions about the question of whether patients treated with anti-TNF-α agents are at increased risk of infections. The performance of additional research are needed to answer this question.
24251990 Efficacy and safety of reducing duration of infliximab infusion. 2014 Mar OBJECTIVE: To evaluate the safety and efficacy of reducing the duration of infliximab infusion for rheumatoid arthritis (RA) treatment. METHODS: The first 6 infliximab infusions were each administered over a 2-h period. If no adverse reaction was observed, infusion times were shortened to 1 h starting with the seventh infusion with further shortening to 30 min starting with the thirteenth infusion. Subjects were divided into two groups: shortened infusion time group, in which infusion times were shortened as above; and constant infusion time group, in which infusion time was 2 h. Incidence of infusion reactions and improvement in disease activity score for 28 joints (DAS-28) erythrocyte sedimentation rate (ESR) for total infusions were compared for the seventh to twelfth and thirteenth to eighteenth infusions. RESULTS: The incidences of infusion reactions after the seventh to twelfth and thirteenth to eighteenth infusions in the shortened infusion time group were 0.53% and 0.58%, respectively. In the constant infusion time group, these were 0.70% and 0.67%, respectively. Furthermore, shortening the infusion duration did not affect the DAS-28 (ESR) improvement rate. CONCLUSIONS: We established that this stage-wise shortening of infusion duration, first to 1 h and then to 30 min, did not compromise the safety or efficacy of treatment.
24432363 Quantitative assessment of synovitis in patients with rheumatoid arthritis using fluoresce 2013 INTRODUCTION: To prospectively evaluate quantitative assessment of fluorescence optical imaging (FOI) for differentiation of synovitic from non-synovitic joints in patients suffering from rheumatoid arthritis (RA). METHODS: FOI of the hands was performed in patients with active RA, and a stratified quantitative fluorescence readout (FLRO) of 3 phases (1-120 s; 121-240 s; 241-360 s) was generated for 5 individual joints of the clinical predominant hand (carpal joint, metacarpophalangeal and proximal interphalangeal joints of digits II & III). To dissect the effect of the overall perfusion of the hand from the perfusion due to synovitis, a fluorescence ratio (FLRA) was additionally calculated, dividing each FLRO by the readout of the eponychium of digit II. The mean FLRO and FLRA were compared between joints with absent vs. present synovitis determined by clinical examination, grayscale, color Doppler ultrasonography, or magnetic resonance imaging (MRI). RESULTS: The analysis for 90 individual joints from 18 patients yielded FLRO ranging from 4.4 to 49.0 × 10(3), and FLRAs ranging from 0.37 to 2.27. Overall, the analyses based on the FLRA revealed a higher discrimination than the analyses related to the FLRO, demonstrating most significant differences in phases 2 and 3. A sensitivity of 26/39 (67%) and a specificity of 31/40 (77%) were calculated for FLRA of phase 3 using a cut-off value of more than 1.2 to detect MRI-confirmed synovitis with FOI. CONCLUSIONS: FOI has a potential for visualizing synovitis in subjects with RA. For adequate FOI interpretation, quantitative analysis should be based on the novel FLRA calculated for phases 2 and 3.
23627398 Tumour necrosis factor antagonist and tuberculosis in patients with rheumatoid arthritis: 2013 Jul Rheumatoid arthritis (RA) is a systemic autoimmune disease in which inflammation of the joints is one of the dominant clinical abnormalities resulting in serious morbidity. Over the past decade, tumour necrosis factor (TNF) antagonist has revolutionized the treatment of RA. However, the subsequent increased risk of developing tuberculosis is one of the major drawbacks of this otherwise effective treatment. Latent tuberculosis infection (LTBI) is an asymptomatic form of tuberculosis that is confined by the host's immune system. Active tuberculosis may develop when the immune status weakens. This risk is much higher in patients receiving TNF antagonist. Traditionally, tuberculin skin test (TST) is used to diagnose LTBI. Unfortunately, TST cannot distinguish bacillus Calmette-Guérin (BCG) vaccination from tuberculosis making it difficult to use as a reliable diagnostic tool. In addition, possible anergy and interaction of the altered autoimmune status in rheumatological diseases further complicate the interpretation of TST results. Although interferon-gamma release assay (IGRA) has improved the diagnosis of LTBI in immunocompetent individuals, its respective sensitivity/specificity values are unknown in patients with autoimmune disease due to variable pretest probability and lack of confirmatory test for LTBI. Thus, the use of IGRA for screening LTBI is variable among different countries. This review explores the prevalence of tuberculosis in patients receiving TNF antagonist in countries with different tuberculosis disease burdens and the potential mechanisms for variation in the incidence of tuberculosis with different TNF antagonists, the current practice guidelines for assessing the risk of LTBI in different countries, and the possible solutions for improving diagnosis, monitoring and management of LTBI.
23802713 Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis. 2013 Aug Symptoms of itch and pain in chronic inflammatory conditions of psoriasis (PS) and rheumatoid arthritis (RA) can highly affect patients' quality of life. Studies in other patient groups indicate that sensitivity to itch and pain is altered in line with the patient's main symptom of either chronic itch or pain, as a result of sensitization processes. This study directly compared whether patients with chronic inflammatory conditions associated with chronic itch or pain display a heightened sensitivity to itch and pain, respectively. Sensitivity to itch and pain was measured by applying stimuli of quantitative sensory testing (QST) in female patients with chronic itch due to PS or chronic pain due to RA. Levels of itch and pain evoked by the QST stimuli as well as the tolerance to the stimuli were determined. Patients with PS reacted to the stimuli with a higher itch response (histamine), while the patients with RA displayed a lowered tolerance to the stimuli (cold pressor test and mechanical stimulation) in comparison with the other patient group. In line with previous studies in other patient groups with chronic itch or pain, further support was found that somatosensory stimuli are processed in line with the patients' main symptom through generic sensitization processes, also in chronic inflammatory conditions such as PS and RA.
23742996 Characterization of chemically defined poly-N-isopropylacrylamide based copolymeric adjuva 2013 Aug 2 PNiPAAm is a thermo-responsive polymer with an adjuvant activity. To identify the minimal chemical structure present within PNiPAAm responsible for its adjuvant property, three different constituent polymers with specific functional groups were synthesized through free radical reaction and tested their adjuvant potential along with PNiPAAm. Among them, polymer with isopropyl attached to an amide showed maximal adjuvant activity in rodents followed by polymer with amide or ketone functional groups. However, secondary amine containing polymer did not show any adjuvant activity. In addition, to improve the adjuvant properties of PNiPAAm, we incorporated an affinity ligand, boronate. At first, we synthesized and characterized the dual responsive copolymers PNiPAAm-co-VPBA and PNiPAAm-co-VPBA-co-DMAEMA. Biocompatibility of these copolymers was confirmed both in vitro and in vivo. Mice injected with these copolymers mixed with collagen (CII) developed significant levels of anti-CII antibodies comprising of all the major IgG subclasses and an increased T cell activation. At the injection site, massive infiltration of immune cells was observed. However, only PNiPAAm-co-VPBA-co-DMAEMA-CII induced arthritis in mice after injection of 0.5M fructose confirming the importance of effective release of CII from the polymer for its adjuvant activity. Thus, a fine balance of hydrophobicity and hydrophilicity promotes adjuvant properties and continuous release of antigen, in this case CII, from polymer is essential for its adjuvant activity.
22730366 Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose 2013 Jun OBJECTIVE: To assess the safety and efficacy of secukinumab, a fully human monoclonal anti-interleukin-17A antibody, in patients with rheumatoid arthritis (RA). METHODS: Patients (n=237) with inadequate response to methotrexate were randomly assigned to receive monthly subcutaneous injections of secukinumab 25 mg, 75 mg, 150 mg, 300 mg or placebo. The primary endpoint was the American College of Rheumatology 20% response (ACR20) at week 16. RESULTS: Demographics and baseline characteristics were comparable across all treatment groups. The primary efficacy endpoint was not achieved: the proportion of ACR20 responders at week 16 with secukinumab 25-300 mg was 36.0-53.7% versus placebo (34%). Disease activity score in 28 joints (DAS28)-C-reactive protein (CRP) was a secondary endpoint and clinically relevant decreases with secukinumab 75-300 mg were reported versus placebo. Serum high sensitivity CRP levels at week 16 were significantly reduced with secukinumab 75 mg, 150 mg and 300 mg doses versus placebo. The safety profile of secukinumab was consistent with that seen with other biological agents. Most adverse events (AE) were mild to moderate in severity. Infections were slightly more frequent with secukinumab than placebo. Six serious AE were reported: secukinumab 75 mg (one), secukinumab 300 mg (four) and placebo (one). CONCLUSIONS: ACR20 response rates differed between secukinumab 75 mg, 150 mg and 300 mg doses and placebo; however, the primary efficacy endpoint was not achieved. Greater decreases in DAS28 were observed with secukinumab 75 mg, 150 mg and 300 mg than placebo. There were no unexpected safety signals and no specific organ-related toxicities. Further trials with secukinumab in the treatment of RA are warranted.
23489057 Palmoplantar subcorneal pustular dermatosis following adalimumab therapy for rheumatoid ar 2013 May BACKGROUND: Tumour necrosis factor (TNF)-α inhibitors represent potent new therapies for severe forms of psoriasis, psoriatic arthritis, and several other immune-mediated disorders. Paradoxical worsening or de novo development of psoriasis has been documented with their use. Palmoplantar pustulosis has been one of the commoner presentations of this unusual side effect. Subcorneal pustular dermatosis (SPD) has some similarity to pustular psoriasis, particularly the acral form of SPD. Thus far there have been no biopsy-proven cases of SPD associated with TNF-α inhibitor use. METHODS: We describe clinical and histopathological features of a pustular skin condition which occurred in a 48-year-old woman with rheumatoid arthritis who had started adalimumab four months prior. The adalimumab had been added to her usual treatment with methotrexate because of incomplete symptom control. RESULTS: Painful and pruritic skin lesions were noted on her palms and soles primarily, with some extension to the limbs and abdomen. Examination revealed relatively non-inflamed pustules with fluid levels, together with sparse crusted papules. Histopathology showed subcorneal pustules more suggestive of SPD than pustular psoriasis. The eruption resolved completely when adalimumab was withdrawn; methotrexate was continued. CONCLUSION: Subcorneal pustular dermatosis, in addition to psoriasis vulgaris and pustular psoriasis, may occur in patients treated with TNF-α inhibitors like adalimumab.