B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: A six‐month,national, multicenter,open‐label study

Objective

To examine whether serum B cell markers can predict response to rituximab, a B cell–depleting monoclonal antibody, in patients with refractory rheumatoid arthritis (RA).

Methods

This rituximab re‐treatment dose study (SMART [eSsai MAbthera sur la dose de Re‐Traitement]) involved 208 patients with refractory RA. Serum markers of B cell activation (anti–cyclic citrullinated peptide [anti‐CCP] antibodies, rheumatoid factor [RF], serum IgG, IgA, and IgM levels, serum κ and λ free light chains, and serum BAFF) were assessed before the first rituximab cycle (1,000 mg on days 1 and 15). Univariate and multivariate analyses were performed to identify factors associated with a European League Against Rheumatism (EULAR) response at 24 weeks.

Results

There were 149 responders (72%). Two baseline factors were associated with a EULAR response at 24 weeks in multivariate analysis: the presence of anti‐CCP antibodies or RF (odds ratio 3.5 [95% confidence interval 1.6–7.6]) and a serum IgG concentration above normal (odds ratio 2.11 [95% confidence interval 1.02–4.33]), with synergy between them (odds ratio 6.0 [95% confidence interval 2.2–16.2]).

Conclusion

The presence of RF or anti‐CCP antibodies and elevated IgG are 2 simple biomarkers that can be used routinely before therapy to predict response to rituximab in patients with refractory RA.

     

Differential effects of fibromodulin deficiency on mouse mandibular bones and teeth: a micro-CT time course study

Fibromodulin (Fmod) is a keratan sulfate small leucine-rich proteoglycan which is enriched in bones and teeth. In order to determine its functions on bone and tooth mineralization we characterized the phenotype of Fmod-deficient (Fmod-KO) mice using a new-generation microfocus computerized tomography system (micro-CT) and software allowing advanced visualization of 3-D data. Three-week-old and 10- week-old Fmod-KO mandibles and teeth were compared with those of age-matched wild-type (WT) mice. In both young and mature mice the Fmod-KO mandibles were hypomineralized, especially the posterior (proximal) part of the mandible as it appeared to be the main target of the molecule deficiency whereas less extensive alterations were found in the alveolar bone. In transverse sections, larger marrow spaces were observed in the Fmod-KO mice compared with age-matched young or mature WT mice. Quantitative evaluation of the pulp volume of the first molar and 3-D reconstructions suggested that dentinogenesis was diminished in 3-week-old Fmod-KO teeth. In contrast, increased dentin formation was found in 10-week-old Fmod-KO mice and it was accompanied by a reduced pulp volume. Thus, the differential effects of Fmod deficiency on bones and teeth appear to diverge in adult mice. This may result from the previously reported differences in the molecular weight of Fmod in the 2 tissues or from compensatory mechanisms due to the overexpression of DSP and DMP-1 in the dental pulp of Fmod-KO. It is also possible that a single molecule plays diverging roles in a tissue-specific or region-specific manner.     

Ophthalmic features of systemic diseases

The eye is intricately integrated with the functions of the body. Ocular changes may precede or run concurrently with various systemic conditions and often represent important prognostic indicators of disease progression. In addition to a thorough diagnostic evaluation and treatment of underlying processes, individuals with systemic diseases and concurrent ocular changes may need comprehensive ophthalmic examination to reduce the risk of visual impairment and morbidity. In this review the authors highlight the clinically relevant ocular signs that occur parallel with systemic conditions. In particular, the study focuses on the varied clinical presentations that can lead to rapid diagnosis to improve management of eye disorders that accompany systemic diseases.     

Dental stem cells: Progress and perspectives

Dental pulp stem cells (DPSCs) are thought to contribute to reparative dentin formation, and that they may correspond to heterogenous populations of precursor cells or represent distinct differentiation stages along the odontoblastic lineage. DPSCs share many similarities with mesenchymal stem cells of the bone marrow (BMSCs). It appears that the distribution of tissue stem cells is not random and, within the dental pulp, there are potentially several distinct niches of stem/progenitor cells. In addition to DPSCs, other dental stem cell populations have been isolated. As for DPSCs, further studies are still needed to evaluate their potential of differentiation and their regenerative activity. Up today, (1) the formal demonstration that pulpal resident stem cells are actually the reparative dentin-forming cells recruited in response to injury is still lacking; and (2) the origin, localization and precise identity of odontogenic stem cells remain largely unknown. Dental clonal cell lines may represent valuable tool to answer some fontamental questions concerning the dental stem cell biology. Altogether, the presence of dental cell populations displaying stem cell properties has opened new paths for considering regenerative therapies. This might be a prerequisite to design alternative strategies for capping and endodontic treatment, using stem cells.     

Therapy-related acute myeloid leukemia: role of DNA repair

The survival improvement of patients treated with chemotherapy or radiotherapy for malignancies are increasing therapy-related acute myeloid leukemia (t-AML). It was thought to be the direct consequence of genetic events induced by such treatments. We here review the mechanisms of specific chemotherapy-related DNA damage inducing the chromosomal or genomic abnormalities characteristic of t-AML. We also focus on how such aberrations could initiate or participate to leukemogenesis. However, only a part of patients exposed to cytotoxic therapy is developing t-AML, suggesting that some genetic predisposition may be involved such as polymorphisms in genes related to DNA repair.     

An open-label, single-arm, phase 2 trial of panitumumab plus FOLFIRI as second-line therapy in patients with metastatic colorectal cancer

Background

This prospective analysis evaluated the effect of tumor KRAS status on efficacy of second-line panitumumab plus folinic acid/5-fluorouracil/irinotecan (FOLFIRI).

Methods

This phase 2, open-label, single-arm study enrolled patients with unresectable, measurable metastatic colorectal cancer (mCRC) after failure of first-line treatment with oxaliplatin-based chemotherapy plus bevacizumab. Patients received panitumumab 6 mg/kg plus FOLFIRI every 2 weeks until disease progression or intolerability. Tumor assessments per Response Evaluation Criteria in Solid Tumors (RECIST) were performed by the investigators every 8 weeks from weeks 8-32 and every 12 weeks thereafter. KRAS status was determined by real-time polymerase chain reaction (PCR) on DNA extracted from fixed tumor sections. Efficacy endpoints included objective response rate, progression-free survival (PFS), and overall survival (OS). Safety endpoints included incidence of adverse events (AEs). Endpoints were evaluated by tumor KRAS status.

Results

Of 116 patients enrolled, 109 patients with known tumor KRAS status received treatment; 59% had wild-type KRAS, and 41% had mutant KRAS. Fifteen patients (23%) with wild-type KRAS and 7 patients (16%) with mutant KRAS had a complete or partial response to treatment. Median PFS was 26 weeks (95% CI, 19-33 weeks) and 19 weeks (95% CI, 12-25 weeks) in the wild-type KRAS and mutant KRAS strata, respectively. Median OS was 50 weeks (95% CI, 39-76 weeks) and 31 weeks (95% CI, 23-47 weeks) in wild-type KRAS and mutant KRAS strata, respectively. Skin-related toxicities (86% of all patients) and diarrhea (74%) were the most common AEs.

Conclusion

Panitumumab plus FOLFIRI numerically improved objective response rate, PFS, and OS in favor of patients with wild-type KRAS tumors. The safety profile was consistent with panitumumab plus FOLFIRI trials in similar patient populations.     

Nephrotoxicity induced by chromium (VI) in adult rats and their progeny

To assess kidney damages in pregnant and lactating rats and in their suckling pups, Wistar female rats were given, through drinking water, 700 parts per million (ppm) of K(2)Cr(2)O(7) from the 14th day of pregnancy until day 14 after delivery. Toxicity was objectified by a significant increase in malondialdehyde (MDA), glutathione (GSH) and nitric oxide (NO) levels in kidney of chromium-treated mothers and their suckling pups. Moreover, lactate dehydrogenase (LDH) was increased in kidney and decreased in plasma of K(2)Cr(2)O(7)-treated rats. Activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) were increased in dams and decreased in their pups. Interestingly, these biochemical modifications were accompanied by higher plasma and lower urinary levels of creatinine, a specific indicator of glomerular function, and of urea than those of controls. Significant increase in creatinine clearance was also found in treated mothers and in their progeny. Histological studies showed an infiltration of mononuclear cells, necrosis and vascular congestion in kidney of pups and dams. Based on the present findings, K(2)Cr(2)O(7) administrated to female rats during late pregnancy and early postnatal periods provoked kidney damages in dams and their offspring.