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ID PMID Title PublicationDate abstract
27790001 Tocilizumab, a humanized anti-interleukin-6 receptor antibody, for treatment of rheumatoid 2011 Interleukin (IL)-6 has a variety of biological functions. For example, it stimulates the production of acute-phase reactants (C-reactive protein and serum amyloid A) and hepcidin which interferes with iron recycling and absorption, causing iron-deficient anemia, and augments expression of vascular endothelial growth factor and receptor activator of nuclear factor-κB ligand in synovial cells, leading to neovascularization and osteoclast formation. IL-6 also acts on lymphocytes, not only on B cells to stimulate autoantibody production, but also on naïve T helper cells to promote T(h)17 cell differentiation. Thus, an imbalance between T cell subsets possibly contributes to development of rheumatoid arthritis. Several clinical studies have demonstrated that a humanized anti-IL-6 receptor antibody, tocilizumab, improves clinical symptoms in rheumatoid arthritis. Tocilizumab prevented radiographic progression of joint destruction by inhibiting cartilage/bone resorption. Tocilizumab also improved hematological abnormalities, including hypergammaglobulinemia, high levels of autoantibodies, and elevation of erythrocyte sedimentation rate and acute-phase proteins. Importantly, tocilizumab improved quality of life by reducing systemic symptoms, including fatigue, anemia, anorexia, and fever. These findings have confirmed that hyperproduction of IL-6 is responsible for the above clinical symptoms, including joint destruction. Many patients treated with tocilizumab achieved clinical remission associated with decreased serum IL-6, suggesting that IL-6 enhances autoimmunity. Tocilizumab is a new therapeutic option for rheumatoid arthritis.
22393626 [Adult-onset Still's disease: case report in Dakar, Senegal]. 2011 Dec Adult-onset Still's disease is a uncommon form of inflammatory rheumatism. It has rarely been reported in black Africa. The purpose of this report is to describe a case in a 49-year-old woman from Dakar, Senegal.
21888689 Challenges in understanding Sjögren's syndrome--improved insights into the pathogenesis g 2011 Aug 19 The reviews in this series on Sjögren syndrome provide an up-to-date summary and perspectives on the pathogenesis of this interesting entity with glandular and frequently systemic manifestations, the value of preclinical models, and our current understanding of therapeutic approaches. The last of these includes what has been learned from trials blocking tumor necrosis factor and, more recently, anti-CD20 therapy. Potential therapeutic targets, such as blockade of the B cell-activating factor, the role of interferon-alpha, and targeting CD22, are discussed.
27789999 Involvement of CX3CL1/CX3CR1 axis in etanercept therapy for patients with active rheumatoi 2011 OBJECTIVE: To examine the relationship between serum chemokine levels and patient responsiveness in rheumatoid arthritis (RA) patients to etanercept (ETN) and the influence of ETN administration on serum chemokine levels. METHODS: Serum levels of the chemokines CX3CL1, CXCL8, CXCL10, and CCL3 were quantified prior to (at baseline) and after 14 weeks of treatment with ETN in 20 patients using enzyme-linked immunosorbent assay. Disease status was assessed using the Disease Activity Score (DAS28). The response to ETN was classified according to the European League Against Rheumatism (EULAR) response criteria. RESULTS: By 14 weeks, ETN produced a significant overall reduction in DAS28 among the 20 patients with RA; eight patients achieved a good response, and 10 patients achieved a moderate response based on EULAR response criteria. A significant reduction in CX3CL1 was observed in the responsive group, although ETN treatment had no significant effect on the serum levels of the other three chemokines. In addition, the messenger ribonucleic acid expression of CX3CR1 in peripheral blood mononuclear cells and the cell-surface expression of CX3CR1 protein in peripheral blood CD8(+)CD3(+) T cells were both decreased after ETN treatment. CONCLUSIONS: Our results suggest that the CX3CL1 and CX3CR1 in patients with active RA may be sensitive to antitumor necrosis factor-α therapy and confirm that CX3CL1/CX3CR1 axis plays a crucial role in the pathogenesis of RA.
24155514 Reduction of CXCR4 expression in Rheumatoid Arthritis Rat Joints by low level diode laser 2011 BACKGROUND: Rheumatoid arthritis (RA) is an inflammatory joint disorder, whose progression leads to the destruction of cartilage and bone. Chemokines and their receptors are potential therapeutic targets in RA. Among these, it has been suggested that CXC chemokine 4 (CXCR4) and its ligand CXC ligand 12 (CXCL12) are involved in RA pathogenesis. Low-level laser irradiation (LLLI) is currently being evaluated for the treatment of RA; however, the molecular mechanisms underlying its effectiveness remain unclear. AIM: To understand the anti-inflammatory effect of LLLI, we used the collagen-induced arthritis (CIA) rat as RA model and analyzed the gene expression profile in synovial membrane in the hindpaw joints of control, CIA and CIA + LLLI. Expression of CXCR4 and CXCL12 genes were also studied. MATERIALS AND METHODS: Total RNA was isolated from the synovial membrane tissue of CIA rat joints or CIA joints treated with LLLI (830 nm Ga-Al-As diode), and gene expression profiles were analyzed by DNA microarray (41,000 rat genes). The mRNA levels were confirmed by reverse transcription polymerase chain reaction (RT-PCR) and real-time PCR. Immunohistochemical examination to examine CXCR4 protein expression was also carried out. RESULTS: DNA microarray analysis showed that CXCR4 gene expression was increased in CIA tissue and LLLI treatment significantly decreased CIA-induced CXCR4 mRNA levels. In contrast, CXCL12 did not show any significant changes. The microarray data of CXCR4 mRNA levels were further validated using RT-PCR and real-time PCR. Increased CXCR4 mRNA levels by CIA and its reduction following LLLI was successfully confirmed. CXCR4 production was increased in CIA joints and its production was decreased by LLLI. CONCLUSION: Decreased CXCR4 expression may be one of the mechanisms in LLLI-mediated reduction of RA inflammation.
21337132 Prevalence of IgA class antibodies to cyclic citrullinated peptide in patients with inflam 2011 Jul Determine the prevalence of anti-CCP isotype IgA and its relation to peripheral arthritis in patients with inflammatory bowel disease (IBD). In a population-based cohort of 654 patients with a definitive diagnosis of IBD, 521 patients were clinically examined by a rheumatologist 6 years after IBD diagnosis Blood serum samples of 416 of these patients were available and analyzed. Antibodies against cyclic citrullinated peptides anti-CCP IgA were determined in the serum samples by an immunofluoresence technique ELiA TM. Among the 416 IBD patients, 5 had a positive IgA class anti-CCP, giving a prevalence of 1.2%. Only four anti-CCP IgA-negative patients had a positive rheumatoid factor IgM, compared to two out of five anti-CCP IgA-positive IBD patients (10.2% versus 40.0%; p = 0.002). There were four patients with rheumatoid arthritis, two in each patient population (0.5% versus 40.0%; p = 0.0007). Four of the five anti-CCP IgA-positive IBD patients had arthritis, two with rheumatoid arthritis, and two with other arthritis. In this first study on the prevalence of IgA anti-CCP antibodies in IBD patients, we demonstrate a low prevalence, but these antibodies are associated with arthritis and positive IgM rheumatoid factor in IBD patients.
25019035 TNF-α Antagonist and Infection in Rheumatoid Arthritis. 2012 May BACKGROUND: Anti-TNF treatment may increase infection risk, although this has been difficult to study because the timing of anti-TNF treatment is driven by disease activity, which may influence infection susceptibility leading to confounding that varies over time. We evaluated the association between anti-TNF initiation in rheumatoid arthritis (RA) patients on disease modifying anti-rheumatic drugs (DMARD) and infection using multiple approaches adjusting for time-varying confounding. METHODS: 383 anti-TNF-naïve RA patients on ≥1 non-biologic-DMARD at enrollment from the Brigham and Women's Rheumatoid Arthritis Sequential Study (BRASS) were followed up to two years. Pooled logistic regressions estimated the association between anti-TNF and infection by including time-varying covariates in the adjusted models and inverse probability treatment weighting (IPTW). RESULTS: Adjustment for time-varying disease activity and other suspected confounders yielded non-statistically significant positive associations between anti-TNF start and infection regardless of analytic approach (RR(mvar_adj) = 2.1, 95% CI: 0.8 - 5.8). CONCLUSIONS: Incorporating changing clinical status, and treatment indications and consequences, yielded consistently (though not significantly) elevated relative risks of infection associated with anti-TNF initiation. Due to limited statistical power, we cannot draw firm conclusions. However, we have illustrated multiple approaches adjusting for potential time-varying confounding in longitudinal studies and hope to replicate the approaches in larger studies.
23119159 Silicon, a Possible Link between Environmental Exposure and Autoimmune Diseases: The Case 2012 Silicon is one of the most common chemicals on earth. Several compounds such as silica, asbestos, silicone or, nanoparticles are built from tetrahedral units with silicon as the central atom. Despite these, structural similarities, they have rarely been analyzed as a group. These compounds generate significant biological alterations that include immune hyperactivation, production of the reactive species of oxygen and tissue injury. These pathological processes may trigger autoimmune responses and lead to the development of rheumatoid arthritis. Populations at risk include those that constantly work in industrial process, mining, and agriculture as well as those that undergo silicone implants. Herein a review on the main features of these compounds and how they may induce autoimmune responses is presented.
23269860 Systematic review and network meta-analysis of combination and monotherapy treatments in d 2012 BACKGROUND: Biologic disease-modifying antirheumatic drugs (bDMARDs) extend the treatment choices for rheumatoid arthritis patients with suboptimal response or intolerance to conventional DMARDs. The objective of this systematic review and meta-analysis was to compare the relative efficacy of EU-licensed bDMARD combination therapy or monotherapy for patients intolerant of or contraindicated to continued methotrexate. METHODS: Comprehensive, structured literature searches were conducted in Medline, Embase, and the Cochrane Library, as well as hand-searching of conference proceedings and reference lists. Phase II or III randomized controlled trials reporting American College of Rheumatology (ACR) criteria scores of 20, 50, and 70 between 12 and 30 weeks' follow-up and enrolling adult patients meeting ACR classification criteria for rheumatoid arthritis previously treated with and with an inadequate response to conventional DMARDs were eligible. To estimate the relative efficacy of treatments whilst preserving the randomized comparisons within each trial, a Bayesian network meta-analysis was conducted in WinBUGS using fixed and random-effects, logit-link models fitted to the binomial ACR 20/50/70 trial data. RESULTS: The systematic review identified 10,625 citations, and after a review of 2450 full-text papers, there were 29 and 14 eligible studies for the combination and monotherapy meta-analyses, respectively. In the combination analysis, all licensed bDMARD combinations had significantly higher odds of ACR 20/50/70 compared to DMARDs alone, except for the rituximab comparison, which did not reach significance for the ACR 70 outcome (based on the 95% credible interval). The etanercept combination was significantly better than the tumor necrosis factor-α inhibitors adalimumab and infliximab in improving ACR 20/50/70 outcomes, with no significant differences between the etanercept combination and certolizumab pegol or tocilizumab. Licensed-dose etanercept, adalimumab, and tocilizumab monotherapy were significantly better than placebo in improving ACR 20/50/70 outcomes. Sensitivity analysis indicated that including studies outside the target population could affect the results. CONCLUSION: Licensed bDMARDs are efficacious in patients with an inadequate response to conventional therapy, but tumor necrosis factor-α inhibitor combination therapies are not equally effective.
22208655 Primary Sjögren's syndrome: time for prospective cohorts. 2012 Aug Many important clinical questions concerning primary Sjögren's syndrome (pSS) remain, that can only be adequately addressed by prospective cohorts. Thus, a better knowledge of the clinical outcome, the course of disease activity and the risk factors of lymphoma requires the setting up of cohorts with biobanks. The homogeneous collection of clinical data, disease activity, patient-related outcome, and biological samples, including DNA, RNA and serum, is definitively mandatory to determine new biological prognostic factors and identify disease activity markers. Three large prospective cohorts have already started to enroll patients with pSS. This will be highly invaluable for scientists and clinicians to gain a better insight into the pathogenesis of pSS, as well as to identify prognostic markers and new therapeutic targets.
22870473 Tocilizumab: a novel humanized anti-interleukin 6 receptor antibody for the treatment of p 2011 Jun Tocilizumab (TCZ; RoActemra® or Actemra®) is a recombinant humanized monoclonal antibody that acts as an interleukin 6 (IL-6) receptor antagonist. For rheumatoid arthritis (RA), intravenous (IV) TCZ 8 mg/kg every 4 weeks has been approved since 2008 in Japan (where it is also approved for polyarticular juvenile idiopathic arthritis, systemic-onset juvenile idiopathic arthritis and Castleman's disease), and since 2009 in Europe in combination with methotrexate (MTX) for the treatment of moderate to severe active RA in adult patients with inadequate response to, or intolerance of, disease-modifying antirheumatic drug (DMARD) or tumor necrosis factor (TNF) antagonist therapy. It may also be administered as monotherapy in the same dose regimen in patients with methotrexate intolerance or with inadequate response to MTX. Since January 2011 in the United States, the indication for treatment with TCZ for RA patients with an inadequate response to one or more TNF antagonists was extended to patients with moderately to severely active RA, and the recommended starting dose is 4 mg/kg every 4 weeks, with an increase to 8 mg/kg based on clinical response. All of these approvals are based on the effectiveness and safety of the 8 mg/kg dose regimen when administered either as monotherapy or in combination with conventional DMARDs in well-designed clinical studies in adult patients with moderate to severe RA. TCZ at this dose is more effective than placebo, MTX or other DMARDs in reducing disease activity and improving health-related quality of life (HR-QoL). Although there were fewer responses with the 4 mg/kg dose, this dose every 4 weeks was not statistically different to 8 mg/kg when administered in combination with MTX, and this dose is the recommended starting dose in the US. Both doses have also been shown to inhibit structural joint damage in patients with an inadequate response to MTX. Thus, TCZ is an important new treatment option in patients with moderate to severe RA.
23152662 Laser in situ keratomileusis in patients with collagen vascular disease: a review of the l 2012 PURPOSE: To evaluate the current United States Food and Drug Administration (FDA) recommendations regarding laser in situ keratomileusis (LASIK) surgery in patients with collagen vascular diseases (CVD) and assess whether these patients make appropriate candidates for laser vision correction, and offer treatment recommendations based on identified clinical data. METHODS: A literature search was conducted using PubMed, Medline, and Ovid to identify all existing studies of LASIK in patients with collagen vascular diseases. The search was conducted without date limitations. Keywords used for the search included MeSH terms: laser in situ keratomileusis, LASIK, refractive surgery, ocular surgery, and cataract surgery connected by "and" with the following MeSH and natural-language terms: collagen vascular disease, rheumatic disease, systemic disease, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, seronegative spondyloarthropathy, HLA B27, ankylosing spondylitis, reactive arthritis, psoriatic arthritis. The abstracts for all studies meeting initial search criteria were reviewed; relevant studies were included. No prospective studies were found; however, four retrospective case studies were identified that examined LASIK surgery in patients with CVD. Several case reports were also identified in similar fashion. RESULTS: The FDA considers CVD a relative contraindication to LASIK surgery, due largely to the ocular complications associated with disease in the CVD spectrum. However, recent studies of LASIK in patients with CVD indicate LASIK may be safe for patients with very well-controlled systemic disease, minimal ocular manifestations, and no clinical signs or history of dry-eye symptoms. CONCLUSION: LASIK surgery may be safe in patients with rheumatoid arthritis or systemic lupus erythematosus and the seronegative spondyloarthropathies if stringent preoperative criteria are met. Evidence suggests patients with Sjögren's syndrome are not suitable candidates for LASIK.
26057468 A case of preventable pulmonary tuberculosis in a Greenlandic, heavily immune suppressed p 2012 Immune modulating therapy, such as tumour necrosis factor (TNF)-alpha inhibitors, is becoming increasingly more widespread in the treatment of many autoimmune diseases. One of the well-documented side effects of TNF-alpha inhibitors is an increased risk of reactivating latent tuberculosis infection (LTBI). Diagnostic tools available for diagnosing LTBI lack sensitivity and specificity. We report the case of a rheumatoid arthritis (RA) patient at high-risk of reactivation of LTBI, who should have been offered prophylactic anti-tuberculous treatment on two separate occasions: firstly, before initiating anti-TNF-α treatment and secondly, as part of routine tuberculosis contact tracing. He subsequently developed severe pulmonary tuberculosis and was hospitalised for 6 weeks.
23284219 Skin rash on site of application of Dashanga Lepa (polyherbal formulation): A rare and une 2012 Jan Dashanga Lepa is a polyherbal preparation of Ayurveda, used to treat many skin ailments and rheumatoid arthritis. However, its toxicological property has not been reported so far. We report a rare case of cutaneous adverse reaction in the form of skin rash following the application of Dashanga Lepa. A 42-year-old female patient with a Pittakaphalaprakruthi (constitution) developed skin rashes, soon after the application of Dashanga Lepa over the applied area, which disappeared after stopping the suspected drug and starting treatment with Shatadhauta ghritha. The patient was again treated with the same formulation after a span of a month, which led to the reappearance of a similar type of rash. The temporal relationship, positive dechallenge, and rechallenge are strong associations between the event and formulation. No such reaction was noticed by any other patient with the suspected medicine.
21816143 Taurine chloramine inhibits osteoclastogenesis and splenic lymphocyte proliferation in mic 2011 Oct 1 Taurine chloramine (TauCl) is produced by activated neutrophils in the inflammatory joint cavities of rheumatoid arthritis and is known to have anti-inflammatory and anti-arthritic effects. However, the mechanisms underlying the anti-arthritic effect of TauCl have not been elucidated. Here, we investigated that mechanism using a collagen-induced arthritis (CIA) mouse model. DBA/1J mice were immunized with bovine type II collagen to induce CIA and were given daily subcutaneous injections of TauCl from the day of first collagen immunization. Severity of arthritis was scored by paw swelling and the arthritis score system. At the 8th week, mice were sacrificed for histological examination using hematoxylin and eosin, safranin-O and tartrate-resistant acid phosphatase (TRAP) staining. Effects of TauCl on osteoclastogenesis from bone marrow-derived preosteoclasts and proliferation of the lymphocytes obtained from spleens of CIA mice were determined. TauCl significantly attenuated the severity of paw swelling and reduced arthritis score in CIA mice. TauCl treated CIA mice showed significant reductions of synovial inflammation, cartilage damage and bone erosion. The number of TRAP-positive cells in the joints of TauCl treated CIA mice was reduced. TauCl inhibited osteoclastogenesis from the RANKL treated bone marrow-derived preosteoclasts in a dose-dependent manner. TauCl also inhibited the proliferation of splenic lymphocytes obtained from CIA mice. In conclusion, TauCl attenuated the severity of CIA by inhibiting lymphocyte proliferation and osteoclastogenesis. Combined our results suggest that TauCl produced endogenously in inflamed joints may suppress the development of rheumatoid arthritis and that TauCl may be used for therapeutic treatment of rheumatoid arthritis.
22271069 Conjunctival nodule in rheumatoid arthritis. 2012 Feb Conjunctival nodule is very rarely seen in patients with rheumatoid arthritis. Previously reported cases were associated with the use of methotrexate. Here, we report a conjunctival rheumatoid nodule without such prior treatment. A 49-year-old woman with seropositive rheumatoid arthritis, who was being treated only with oral steroids and hydroxychloroquine, developed diffuse anterior scleritis in the right eye. In addition, examination showed a focal raised yellow/tan conjunctival nodule. The nodule was within the bulbar conjunctiva with no attachments to the underlying tissue, which is different from nodular scleritis. The nodule was not tender on palpation. The patient underwent excisional biopsy of the nodule. Intraoperatively, the lesion was noted to be a firm nodule within substantia propria of the conjunctiva. Hematoxylin-eosin staining of the specimen revealed a central area of necrosis surrounded by palisades of histiocytes. Increased dosage of oral steroid after the biopsy resulted in resolution of the ocular symptoms and signs. In conclusion, rheumatoid nodules may be seen in the conjunctiva even without prior treatment with methotrexate. These nodules may show the severity of the underlying disease and the need for more aggressive treatment.
21195061 Etiological role of cigarette smoking in rheumatoid arthritis: Nasal exposure to cigarette 2011 Jan 28 Cigarette smoking is a major environmental risk factor for rheumatoid arthritis (RA). However, the experimental bases supporting the etiological role of cigarette smoking in RA have not been fully provided. We have reported that cigarette smoke condensate (CSC), by means of subcutaneous injection into DBA/1J mice with collagen and complete Freund's adjuvant or intraperitoneal injection one day before immunization, augmented the development of arthritis in the mouse model of collagen type II-induced arthritis (CIA). However, these experimental procedures may not be appropriate for cigarette smoking. In this study, we nasally exposed mice to mainstream CSC and found that CSC augmented the induction and development of arthritis and antibody level against collagen. Histological examination confirmed the augmenting effect of CSC. These findings provide experimental bases supporting the etiological role of cigarette smoking in RA.
21501144 SPA0355, a thiourea analogue, inhibits inflammatory responses and joint destruction in fib 2011 Sep BACKGROUND AND PURPOSE: NF-κB has been implicated as a therapeutic target for the treatment of rheumatoid arthritis. We previously synthesized a thiourea analogue, SPA0355, which suppressed NF-κB activity. Here we have assessed the anti-inflammatory and anti-arthritic effects of SPA0355. EXPERIMENTAL APPROACH: We evaluated the effects of SPA0355 on human rheumatoid fibroblast-like synoviocytes in vitro and on collagen-induced arthritis (CIA) in mice in vivo. KEY RESULTS: In vitro experiments demonstrated that SPA0355 suppressed chemokine production, matrix metalloproteinase secretion and cell proliferation induced by TNF-α in rheumatoid fibroblast-like synoviocytes. In addition, SPA0355 inhibited osteoclast differentiation induced by macrophage colony-stimulating factor and the receptor activator of NF-κB ligand, in bone marrow macrophages. Mice with CIA that were pretreated with SPA0355 had a lower cumulative disease incidence and severity of arthritis, based on hind paw thickness, radiological and histopathological findings, and inflammatory cytokine levels, than mice treated with vehicle. Mice treated with SPA0355, after the onset of CIA, also showed significantly decreased disease incidence and joint oedema. The in vitro and in vivo protective effects of SPA0355 were mediated by inhibition of the NF-κB signalling pathway. CONCLUSION AND IMPLICATIONS: Taken together, these results suggested that using SPA0355 to block the NF-κB pathway in rheumatoid joints reduced both the inflammatory responses and tissue destruction. Therefore, SPA0355 may have therapeutic value in preventing or delaying joint destruction in patients with rheumatoid arthritis.
22570663 A Seropositive Nodular Rheumatoid Polyarthritis without Arthritis: Does It Exist? 2012 The rheumatoid polyarthritis is the most frequent chronic polyarthritis. It affects essentially the woman between 40 and 60 years. Rheumatic subcutaneous nodules and tenosynovitis are usually associated with seropositive symptomatic rheumatoid polyarthritis. It is, however, rare that they constitute the essential clinical expression of the disease. In this case, it makes dispute another exceptional form of rheumatoid arthritis such as rheumatoid nodulosis. A 60-year-old woman was hospitalized for tumefaction of the dorsal face of the right hand evolving two months before. The clinical examination found subcutaneous nodules from which the exploration ended in rheumatoid nodules with tenosynovitis. The evolution after four years was favourable under corticosteroid therapy, methotrexate, and colchicine.
21364052 Diagnostic and prognostic value of antibodies and soluble biomarkers in undifferentiated p 2011 Mar OBJECTIVE: When patients present with undifferentiated peripheral inflammatory arthritis (UPIA), early diagnosis and evaluation of prognostic factors are decisive steps for therapeutic success. We reviewed published evidence on the diagnostic and prognostic performance of autoantibodies and soluble biomarkers in UPIA. METHODS: We conducted a systematic literature search covering studies published until January 2009. Additionally, we screened conference abstracts presented at European League Against Rheumatism and American College of Rheumatology meetings in 2007 and 2008. RESULTS: We included 52 full-text articles and 12 abstracts. The association of anti-cyclic citrullinated peptide antibody (anti-CCP) and rheumatoid factor (RF) with diagnosis of rheumatoid arthritis at followup is compelling, supported by positive likelihood ratios (LR+) ranging between 1.2 and 20.5 for anti-CCP and 1.1 to 13.5 for RF. The same applies to radiographic outcome. For antikeratin antibodies (AKA) and antiperinuclear factor, existing evidence suggests diagnostic usefulness; AKA also showed prognostic value. Diagnostic and prognostic evidence for other autoantibodies and for bone and cartilage biomarkers was scarce, negative, or controversial. CONCLUSION: Among serological tests, unanimous evidence of substantial diagnostic value exists only for anti-CCP and RF, but is scarce for other markers.