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ID PMID Title PublicationDate abstract
31673419 Patient-reported outcomes for tofacitinib with and without methotrexate, or adalimumab wit 2019 OBJECTIVE: To provide the first direct comparison of patient-reported outcomes (PROs) following treatment with tofacitinib monotherapy versus tofacitinib or adalimumab (ADA) in combination with methotrexate (MTX) in patients with rheumatoid arthritis (RA) with inadequate response to MTX (MTX-IR). METHODS: ORAL Strategy (NCT02187055), a phase IIIB/IV, head-to-head, randomised controlled trial, assessed non-inferiority between tofacitinib 5 mg two times per day monotherapy, tofacitinib 5 mg two times per day+MTX and ADA 40 mg every other week+MTX. PROs assessed included the following: Patient Global Assessment of disease activity (PtGA), Pain, Health Assessment Questionnaire-Disability Index, Functional Assessment of Chronic Illness Therapy-Fatigue and 36-Item Short-Form Health Survey (SF-36) summary and domain scores. RESULTS: Substantial improvements from baseline were reported across all PROs in all treatment arms, which, in the majority, met or exceeded minimum clinically important differences. Compared with tofacitinib monotherapy, tofacitinib+MTX combination treatment conferred significantly greater improvements in PtGA, Pain and SF-36 physical component summary scores at month 6. Statistically or numerically greater improvements were often, but not uniformly, reported for combination treatments compared with tofacitinib monotherapy at other time points. CONCLUSION: Treatment with tofacitinib+MTX, ADA+MTX and tofacitinib monotherapy resulted in clinically meaningful improvements in PROs in MTX-IR patients with RA. These were comparatively greater with combination treatments versus tofacitinib monotherapy, although differences between treatment arms were small, limiting our ability to confer clinical meaning. TRIAL REGISTRATION NUMBER: NCT02187055.
31392559 Effects of coenzyme Q10 supplementation on matrix metalloproteinases and DAS-28 in patient 2019 Dec OBJECTIVES: This study aimed to assess the effect of CoQ10 supplementation on serum matrix metalloproteinases (MMPs) and clinical parameters in rheumatoid arthritis (RA) patients. METHOD: In this randomized, double-blind, placebo-controlled trial, 54 RA patients who fulfilled the eligibility criteria (18-56 years, diagnosed at least 6 months ago, with DAS-28 > 3.2) were randomly assigned into two groups to receive 100 mg/day CoQ10 (n = 27) or placebo (n = 27) for 2 months. Serum MMP-1 and MMP-3 levels and clinical status using disease activity score in 28 joints (DAS-28) were assessed before and after supplementation. Data were analyzed using χ2, independent sample t test, paired t test, Wilcoxon, Mann-Whitney, and analysis of covariance. RESULTS: A significant reduction was observed in both CoQ10 and placebo groups in the medians of serum MMP-1 (0.2 to 0.16, P < 0.001), (0.18 to 0.15, P = 0.001); swollen joint count (2 to 0, P < 0.001), (2 to 0, P = 0.009); and the means of DAS-28 (5.01 ± 1.21 to 2.34 ± 0.68, P < 0.001), (4.88 ± 0.96 to 4.04 ± 1.36, P = 0.009) respectively. Serum MMP-3 level increased significantly in placebo group (2.26 to 2.57, P = 0.020), and the MMP-3 changes between groups were significant (P = 0.027). Furthermore, significant reductions were only observed in ESR, pain score, and tender joint count in CoQ10 group compared with baseline (P = 0.001, P < 0.001, and P < 0.001, respectively). Significant differences were observed between two groups in DAS-28, pain score, and swollen and tender joint count after the intervention (P < 0.001, P < 0.001, and P = 0.012 and P < 0.001, respectively). CONCLUSIONS: It seems that CoQ10 may provide a new complementary approach for RA patients.Key Points• CoQ10 supplementation in RA patients attenuated serum MMP-3 level.• CoQ10 supplementation in RA patients improved clinical outcomes and ameliorated disease severity.• CoQ10 may provide a new complementary approach for patients with RA.
31123976 Strongyloides stercoralis infection in a patient with rheumatoid arthritis and type 2 diab 2019 Nov Strongyloides stercoralis (S. stercoralis), a human intestinal nematode, can lead to hyper/disseminated (HD) infection in patients treated with corticosteroids. Here, we report a case of strongyloidiasis in a 58-year-old female with a history of rheumatoid arthritis (RA) and type 2 diabetes mellitus (T2DM). The patient presented with abdominal pain and gastrointestinal (GI) bleeding. Stool was negative for parasitic agents in the first direct smear examination, and the patient with the probable diagnosis of Helicobacter pylori (H. pylori) infection or Crohn's disease received antibiotics and corticosteroids. Parasitic agents were not detected in further direct stool examinations, and the patient with the diagnosis of pneumonia, chronic kidney disease (CKD), ulcerative colitis, sepsis, and candidiasis received fungal, antibiotic, and corticosteroids medications. Low sensitivity of direct smear and the lack of using two methods in diagnosing intestinal parasitic infections led to delayed detection. In the fourth direct stool examination, rhabditiform larva of S. stercoralis was reported. The treatment of corticosteroids was discontinued and albendazole was started. A literature review was conducted by searching Medline, Embase, Scopus, and Web of Science with the keywords S. stercoralis, strongyloidiasis, RA, and T2DM. Our case indicates that screening S. stercoralis infection in high-risk groups, especially those who are candidates for corticosteroids medications, must be implemented using at least two diagnostic techniques.
31116054 Changes in the incidence of cervical lesions owing to the development of rheumatoid arthri 2020 May Objectives: To clarify changes in the incidence of cervical lesions in rheumatoid arthritis (RA) patients with advanced treatment and the impact of cervical lesions on the patients' quality of life (QOL).Methods: Incidence of radiographic cervical lesions in 1333 RA patients in 2015 was compared with that in our 1999 survey. The association between cervical lesions and QOL evaluated using three different patient-based questionnaires was also analyzed.Results: The incidence of atlantoaxial subluxation (AAS), vertical subluxation (VS), and subaxial subluxation (SAS) in 2015 decreased by 50%, 75%, and 5%, respectively, compared to the 1999 survey. Although QOL, evaluated using the Japanese Orthopedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ; specific to myelopathy), deteriorated as the cervical lesion progressed, there was no association between cervical lesion progression and QOL evaluated using the Short Form-8â„¢ (SF-8â„¢; comprehensive health-related QOL). Cervical lesion progression was also associated with QOL deterioration evaluated using the Health Assessment Questionnaire Disability Index (HAQ-DI; specific to RA), but age and disease duration had stronger influences.Conclusion: The incidence of cervical lesions decreased in 2015 compared to 1999. Cervical lesion progression may be associated with QOL deterioration due to myelopathy. Age and disease duration have more impact on disease-specific QOL.
30148443 Reduced quality of life impacts knowledge and type of informed consent in rheumatoid arthr 2019 Mar OBJECTIVES: Informed consent (IC) is an ethical process required in human subject research. Primary objective was to determine factors associated to poor knowledge of IC content (PK) in patients from an early rheumatoid arthritis cohort. METHODS: The cohort initiated in 2004, had assistant and research purposes (NCT03389711). At inclusion, each patient selected 1 of 4 options of the IC form; options ranged from broad consent (patient's data could be used for research) to patient denied to have his/her data used. Once enrolled, patients had regular assessments. Up to May 2017, the cohort had 146 patients with (median, range) follow-up of 8.8 years, (4.3-11.9) and 143 agreed to participate in a cross-sectional study; patients had scheduled rheumatic evaluations; additionally, a social worker applied a questionnaire that addressed objective described. PK was established by the borderline performance method. Multiple regression models were applied to investigate factors associated to PK. RESULTS: At cohort inclusion, patients were primarily middle-aged (38.3±13.1 years) females (88.9%), with high disease activity (DAS28: 5.8 [4.6-6.8)] and poor quality of life (SF-36: 42 [29-59]). All the patients gave broad IC. At study entry, 35-41.3% of them had PK; longer follow-up and lower SF-36 scores at cohort inclusion, were associated to PK. In addition, 79.7% of the patients had DAS28-remission and 67.1% had SF-36 scores within normal range; interestingly, only 49% of the patients considered broad re-consent and these patients had poorer SF-36 emotional subscore than their counterpart (79±23 vs. 87±1, p=0.02). CONCLUSIONS: Poor quality of life impacts the autonomy of RA patients.
30530827 Genetics of rheumatoid arthritis: 2018 status. 2019 Apr Study of the genetics of rheumatoid arthritis (RA) began about four decades ago with the discovery of HLA-DRB1 Since the beginning of this century, a number of non-HLA risk loci have been identified through genome-wide association studies (GWAS). We now know that over 100 loci are associated with RA risk. Because genetic information implies a clear causal relationship to the disease, research into the pathogenesis of RA should be promoted. However, only 20% of GWAS loci contain coding variants, with the remaining variants occurring in non-coding regions, and therefore, the majority of causal genes and causal variants remain to be identified. The use of epigenetic studies, high-resolution mapping of open chromatin, chromosomal conformation technologies and other approaches could identify many of the missing links between genetic risk variants and causal genetic components, thus expanding our understanding of RA genetics.
30472493 The CD25+/CD4+ T cell ratio and levels of CII, CIX and CXI antibodies in serum may serve a 2019 Mar OBJECTIVE: Collagen antibodies in serum are involved in the pathogenesis of Rheumatoid Arthritis (RA). The objective of this study was to identify the subtype of collagen antibodies and T cell subtype distribution in pristane-induced arthritis (PIA) and to clarify their roles in the initiation and maintenance of arthritis. METHODS: Arthritis was induced in Dark Agouti (DA) rats by injection of pristane. The severity was evaluated by macroscopic and microscopic score systems. The alteration of CD25+/CD4+ T cell ratio in rats was detected by flow cytometry. Collagen type II (CII), CIX, or CXI antibody in serum was determined by ELISA. The levels of Nitric oxide (NO) and tartrate-resistant acid phosphatase (TRAP) were measured by kits. RESULTS: The serum levels of CII, CIX, CXI antibodies were significantly increased in RA patients while slightly increased in PIA rats. The ratio of CD25+/CD4+ T cells was significantly higher in RA rats than that in the control group. The serum levels of NO and TRAP in PIA rats and RA patients were higher than that in the control groups, which suggested that the activity of osteoclast was increased in RA. CONCLUSION: The ratio of CD25+/CD4+ T cells plays a pivotal role in the development of PIA. The serum levels of NO and TRAP are inflammatory and osteoclast activity indicators. The serum levels of CII, CIX and CXI antibodies may serve as the clinical diagnostic indicators. These findings are important to our understanding of the pathogenesis of RA, and may provide biomarkers of RA diagnosis and therapeutic targets for the treatment of RA.
29882689 Mid-term clinical outcome of constrained condylar knee prosthesis for patients with rheuma 2019 Jul Objectives: This study retrospectively investigated the mid-term outcome of Legacy constrained condylar knee (LCCK) prosthesis in patients with rheumatoid arthritis (RA) having severe varus/valgus deformity, instability, and/or bone loss. Methods: Between January 2000 and December 2015, LCCK prostheses had been performed in 32 knees of 25 patients with RA, and 23 knees of 17 patients of the postoperative follow-up minimum 2 years were analyzed in this study (Primary: 14 knees, Revision: 9 knees). The average of follow-up duration was 6.9 ± 2.7 years, all were female, and the average of age and RA duration at the surgery was 59.0 ± 9.5 years and 26.6 ± 13.5 years, respectively. Clinical result was analyzed by Knee Society Score (KSS) knee and function at preoperative time and final visit. Imaging outcome was investigated by femoral tibial angle (FTA), four component alignment angles, and radiolucent line at pre-/postoperative time. Results: KSS knee/function scores and radiographic FTAs were improved after operation. Radiolucent lines around components were seen in 17 knees (73.9%), of which only one knee (4.3%) has shown aseptic loosening. The seven-year Kaplan-Meier survivorship analysis resulted in 91.7%. Conclusion: LCCK prosthesis in RA patients was achieved to the excellent mid-term clinical and radiographic result.
30626837 Development of Propionibacterium acnes-associated Sarcoidosis During Etanercept Therapy. 2019 May 15 Although numerous recent studies have reported the development of sarcoidosis in patients treated with tumor necrosis factor alpha (TNF-α) inhibitors, it is unclear whether the pathogenesis of drug-induced sarcoidosis is identical to that of spontaneous sarcoidosis. We herein present the case of a patient who developed sarcoidosis 6 months after the introduction of etanercept as treatment for rheumatoid arthritis. Typical clinical symptoms with noncaseating epithelioid granulomas detected in a mediastinal lymph node specimen were consistent with the diagnosis of sarcoidosis. Immunohistochemistry revealed Propionibacterium acnes in the noncaseating granulomas. The present findings suggest that Propionibacterium acnes is a cause of sarcoidosis, even when the disease is induced by TNF-α inhibitors.
31573471 Quality improvement for rheumatoid arthritis care: results from a focus group. 2020 May OBJECTIVES: Complex treatment decisions in rheumatoid arthritis (RA) affect aspects of patients' physical, psychological and emotional well-being. We aimed to identify key attributes of patient-centered rheumatologic care for adults with RA through a qualitative study using patient focus group discussions in order to guide quality improvement efforts around optimisation of disease management. METHODS: Patients with RA were recruited from a large academic medical centre rheumatology clinic and its affiliate sites over one month and allocated into focus groups led by an experienced moderator. Focus groups were held until thematic saturation was reached. Patients' responses were examined, categorised into themes, and codified independently by three reviewers. We extracted statements identifying common themes from transcripts. RESULTS: Thirteen patients with RA were recruited and allocated into three focus groups. Mean age was 59.1±10.1 years and average RA disease duration was 17.8 years. All participants had experience taking at least one disease-modifying anti-rheumatic drug (DMARD). Following reviewer analysis of patients' responses, six common themes about quality RA care were identified including: the role and use of self-management strategies, the clinical environment, the health care delivery process, attitudes towards medication, insurance and medication access issues, and the impact of disease on lifestyle. CONCLUSIONS: Themes uncovered in focus group discussions related predominantly to the clinical environment and patient-provider communication. These preliminary results identified the need to incorporate operational aspects of health care delivery into our assessment of the RA patient experience and formed the basis of a RA quality improvement programme targeting medication optimisation.
31836935 Lung cancer in rheumatoid arthritis. Is there a need for better risk assessment and screen 2020 Mar Extra-articular manifestations are common in rheumatoid arthritis (RA), with lung involvement being one of the commonest. Apart from interstitial lung disease which is a well-recognized manifestation, it seems that lung cancer has also increased frequency in RA. In fact, recent meta-analyses have suggested that in RA compared with the general population, lymphomas and lung malignancy are more frequent. For the latter, male gender, seropositivity for rheumatoid factor and/or anti-citrullinated protein antibody (ACPA), as well as older age, has been suggested, among others, as risk factors. Several hypotheses have been formulated to explain the increased frequency of lung cancer in RA. These include smoking and/or interstitial lung as common risk factors for both RA and lung cancer and chronic inflammation predisposing to malignant diseases. Numerous questions remain to be answered. For example, are there any risk factors (e.g., positivity for rheumatoid factor or anti-citrullinated peptide antibodies) that would predict the development of lung cancer in these patients? Are there any screening procedures appropriate for early diagnosis and therefore better outcome? Data from large registries are needed to better define the profile of these patients.
31398076 How do neuropathic pain-like symptoms affect health-related quality of life among patients 2020 Sep Objectives: Rheumatoid arthritis (RA) pain is thought to be nociceptive. However, recent studies indicate that RA also involves the neuropathic pain (NP) mechanism. We examined pain features and the effect of NP-like symptoms on health-related quality of life (HRQOL) among patients with RA.Methods: The painDETECT questionnaire (PDQ) was used to evaluate NP-like symptoms among 145 outpatients with RA. Disease activity, pain quality, and HRQOL were evaluated. We compared clinical parameters between patients with and without NP-like symptoms and analyzed pain features and the effect of NP-like symptoms on HRQOL, along with multiple other pain-related parameters.Results: Thirty (20.7%) patients had NP-like symptoms (PDQ ≥13). Patient global assessment and evaluator global assessment diverged for patients with RA who had NP-like symptoms. Of the examined pain-related parameters, PDQ score (p = .038, ß = -.173) was associated with the Short-Form 36-Item Health Survey role-social component summary score, but not with the physical or mental component summary scores.Conclusion: NP-like symptoms affected HRQOL among patients with RA. There was discordance between global assessments by patients and by evaluators for patients with RA who had NP-like symptoms. Therefore, NP-like symptoms should be given somewhat more attention when treating patients with RA.
30332708 [Predictors of Ambulatory Medical Care Utilization by the Elderly with Osteoarthritis, Rhe 2019 Nov BACKGROUND: Since chronic musculoskeletal disorders (MD) cause considerable costs for the German health care system, service providers and policy makers need information on the use of the different health care services. On the basis of Andersen's behavioral model, the article provides predictors of ambulatory medical care utilization in the fields of general medicine, orthopaedics and physiotherapy relevant to chronic MD in the 65- to 79-year-old population affected by arthritis, rheumatoid arthritis or osteoporosis in Germany. METHODS: Based on data of the first wave of the German Health Interview and Examination Survey for Adults (DEGS1) relationships between ambulatory medical care utilization and explanatory variables were analysed using models for count data. RESULTS: An increased use of general medicine is associated with individual disease factors (considerable health restriction: incidence rate ratio (IRR) 1.64 (1.18-2.27); joint pain: IRR 1.38 (1.06-1.79)). An increased use of orthopaedics is associated with an increased use of general medicine (IRR 1.05 (1.01-1.10)) and an increased use of physiotherapy is determined by structural as well as individual factors (eastern Germany (including Berlin): IRR 0.66 (0.47-0.93); considerable health restriction: IRR 1.84 (1.09-3.12); increased use of orthopaedics: IRR 1.07 (1.01-1.14). CONCLUSION: As expected, individual disease factors play an important part in explaining the use of health care services. Concurrently, the absence of comorbidity reveals a previously unidentified predictor of a decreased use of general medicine by those with chronic MD.
30132352 Combined treatment with omalizumab and etanercept in a patient with chronic spontaneous ur 2019 Jun We present a case report of a 64-year old female patient with rheumatoid arthritis and chronic spontaneous urticaria. She was treated with a combination of etanercept and omalizumab with good results and no adverse effects. In selected patients with severe inflammatory disease activity it is worth considering combined biologic therapy. However, treatment should be closely monitored as short-term and long-term side effects are not properly elucidated.
31200245 Innovative HPTLC method for simultaneous determination of ternary mixture of certain DMARD 2019 Aug 15 A uniquely developed high performance thin-layer chromatographic (HPTLC) method coupled with UV detection was applied using quality by design approach (QbD) for simultaneous determination of methotrexate (MTX), sulfasalazine (SSZ) and hydroxychloroquine (HCQ) in serum and urine samples of rheumatoid arthritis patients. MTX, SSZ with HCQ are the most common disease-modifying antirheumatic drugs (DMARDs) combination used for the treatment of rheumatoid arthritis. This ternary mixture with montelukast (MK) added as internal standard, were separated by using a mixture of ethyl acetate: methanol: 25% ammonia, (8: 2: 3, v/v/v) as a mobile phase system. The separation was achieved on HPTLC precoated silica gel plate 60 F(254) and the detection was carried out at 306 nm for MTX and at 340 nm for both SSZ and HCQ. The design was planned to obtain the most optimum retardation factors (R(f)) with best resolution. The R(f) values for MTX, SSZ, MK and HCQ were of 0.31 ± 0.03, 0.62 ± 0.02, 0.71 ± 0.02 and 0.83 ± 0.03; respectively. The interactive response optimizer achieved the most favorable conditions with acceptable composite desirability of 0.9703. Linear relationship with good correlation coefficients (r = 0.9990-0.9994) were also obtained with detection and quantification limits of 13.94-260.64 and 46.84-1810.01(ng/ml); respectively. The suggested method was established in accordance with the guidelines of Food and Drug Administration (FDA). The established QbD-HPTLC method achieved simple, sensitive and selective quantification of the studied drugs in serum and urine samples in the presence of their metabolites with no interferences. This method can be extended effectively for therapeutic drug monitoring and pharmacokinetics studies of these drugs.
31076945 Efficacy of rituximab in resistant palindromic rheumatism: first report in literature. 2019 Sep BACKGROUND: Rituximab (RTX) provides significant clinical benefits in active rheumatoid arthritis (RA) patients with inadequate response to DMARDs and anti-TNF. There is no data regarding efficacy of RTX in seropositive Palindromic Rheumatism (PR), a forerunner of RA. AIM: To determine the efficacy and safety of RTX treatment in active PR patients exhibiting inadequate response to conventional synthetic DMARDs (csDMARDs). METHODS: The retrospective study, over a period of 3 years, included seropositive (RF ± antiCCP) PR patients with inadequate control of PR (> 4 attacks per months) despite combination csDMARDs and were treated with RTX. All the patients were treated with an initial dose of 500 mg RTX and later with a second infusion after 2 weeks' period in those who did not achieve adequate/ complete disease control. Patients were continued on csDMARDS and retreated with RTX on relapse of symptoms. RESULTS: Thirty-three seropositive PR patients with a mean age of 48.15 ± 14.2 years, mean disease duration of 68.4 ± 68.2 months, mean follow up period of 24.3 ± 10.8 months, were treated with RTX. 88% patients were on combination DMARDS and 79% patients were females. All patient achieved rapid and complete control of palindromic attacks with RTX. Fifteen patients had a relapse after a mean duration of 10.4 ± 5.5 months and needed repeat RTX infusions following which remission was achieved. None of the patients progressed to RA till the end of the follow-up. No serious adverse effects were recorded. CONCLUSION: RTX treatment could be effective in achieving disease control in active palindromic rheumatism not responding to csDMARDs. KEY POINTS: • PR is thought to be a forerunner of RA and rituximab (RTX) has been found to be effective in RA. • Our study supports the hypothesis that B cells play an important role in the pathophysiology of PR and that the combination (RTX+ conventional drugs) can prevent the disease evolution into RA. • This 3-year retrospective study showed that rituximab was found to be effective in those who responded poorly to conventional drugs and remission was achieved in all patients. • Although it is a rare disease, we see palindromic rheumatism patients in India more often. As the symptoms are very debilitating in these patients, in those patients, not controlled on conventional drugs, rituximab offers newer promise in controlling the attacks and prevents further progression to RA.
30713294 Methotrexate-associated Lymphoproliferative Disorder: A Rare Differential Diagnosis of Whe 2019 Jun 15 A 70-year-old woman was admitted for the evaluation of wheezes and a nodular lesion in the left lung field. She had been diagnosed with rheumatoid arthritis at 45 years of age and was continuously treated with methotrexate (MTX) at 8 mg/week. Bronchoscopic aspiration histology of a hilar lymph node suggested a lymphoproliferative disorder (LPD). After discontinuation of MTX, the lung nodule and wheezes disappeared. Although wheezes are not a usual manifestation of LPD, her clinical course clearly demonstrated an obvious relationship between LPD-induced airway narrowing and wheezes.
30132861 Exosome-encapsulated miR-6089 regulates inflammatory response via targeting TLR4. 2019 Feb Exosome-encapsulated microRNAs (miRNAs) have been identified as potential biomarkers in autoimmune diseases. However, little is known about the role of exosome-delivered miRNAs in rheumatoid arthritis (RA). In this study, we investigated the profile of specific exosomal miRNAs by microarray analysis of serum exosomes from three patients with RA and three healthy controls. Quantitative real-time PCR (qRT-PCR) was performed to validate the aberrantly expressed exosomal miRNAs. A total of 20 exosome-encapsulated miRNAs were identified to be differently expressed in the serum of patients with RA compared with controls. Interestingly, we found that exosome-encapsulated miR-6089 was significantly decreased after validation by qRT-PCR in serum exosomes from 76 patients with RA and 20 controls. Besides, miR-6089 could inhibit lipopolysaccharide (LPS)-induced cell proliferation and activation of macrophage-like THP-1 cells. TLR4 was a direct target for miR-6089. MiR-6089 regulated the generation of IL-6, IL-29, and TNF-α by targetedly controlling TLR4 signaling. In conclusion, exosome-encapsulated miR-6089 regulates LPS/TLR4-mediated inflammatory response, which may serve as a novel, promising biomarker in RA.
31486005 Targeting Granulocyte-Monocyte Colony-Stimulating Factor Signaling in Rheumatoid Arthritis 2019 Nov Rheumatoid arthritis (RA) is a systemic, autoimmune disease that affects joints and extra-articular structures. In the last decade, the management of this chronic disease has dramatically changed with the introduction of several targeted mechanisms of action, such as tumor necrosis factor-α inhibition, T-cell costimulation inhibition, B-cell depletion, interleukin-6 blockade, and Janus kinase inhibition. Beyond its well-known hematopoietic role on the proliferation and differentiation of myeloid cells, granulocyte-monocyte colony-stimulating factor (GM-CSF) is a proinflammatory mediator acting as a cytokine, with a proven pathogenetic role in autoimmune disorders such as RA. In vitro studies clearly demonstrated the effect of GM-CSF in the communication between resident tissue cells and activated macrophages at chronic inflammation sites, and confirmed the elevation of GM-CSF levels in inflamed synovial tissue of RA subjects compared with healthy controls. Moreover, a pivotal role of GM-CSF in the perception of pain has been clearly confirmed. Therefore, blockade of the GM-CSF pathway by monoclonal antibodies directed against the cytokine itself or its receptor has been investigated in refractory RA patients. Overall, the safety profile of GM-CSF inhibitors seems to be very favorable, with a particularly low incidence of infectious complications. The efficacy of this new mechanism of action is comparable with main competitors, even though the response rates reported in phase II randomized controlled trials (RCTs) appear to be numerically lower than the response rates observed with other biological disease-modifying antirheumatic drugs already licensed for RA. Mainly because of this reason, nowadays the development program of most GM-CSF blockers for RA has been discontinued, with the exception of otilimab, which is under evaluation in two phase III RCTs with a head-to head non-inferiority design against tofacitinib. These studies will likely be useful for better defining the potential role of GM-CSF inhibition in the therapeutic algorithm of RA. On the other hand, the potential role of GM-CSF blockade in the treatment of other rheumatic diseases is now under investigation. Phase II trials are ongoing with the aim of evaluating mavrilimumab for the treatment of giant cell arteritis, and namilumab for the treatment of spondyloarthritis. Moreover, GM-CSF inhibitors have been tested in osteoarthritis and diffuse subtype of systemic sclerosis. This review aims to describe in detail the available evidence on the GM-CSF blocking pathway in RA management, paving the way to a possible alternative treatment for RA patients. Novel insights regarding the potential use of GM-CSF blockers for alternative indications will be also addressed.
31304568 Towards a Better Classification and Novel Therapies Based on the Genetics of Systemic Scle 2019 Jul 15 PURPOSE OF THE REVIEW: Nowadays, important advances have occurred in our understanding of the pathogenesis of systemic sclerosis (SSc), which is a rare immune-mediated inflammatory disease (IMID) characterized by vascular damage, immune imbalance, and fibrosis. Its etiology remains unknown; nevertheless, both environmental and genetic factors play a major role in the disease. This review will focus on the main advances made in the field of genetics of SSc. RECENT FINDINGS: The assessment of how interindividual genetic variability affects disease onset and progression has enhanced our knowledge of disease biology, and this will eventually translate in the development of new diagnostic and therapeutic tools, which is the final goal of personalized medicine. We will provide an overview of the most relevant achievements in the genetics of SSc, its shared genetics among IMIDs with special attention on drug repurposing, current challenges for the functional characterization of risk variants, and future directions.