Impact of DMARD treatment and systemic inflammation on all-cause mortality in patients with rheumatoid arthritis and interstitial lung disease: a cohort study from the German RABBIT register.

OBJECTIVES: To investigate the impact of disease activity and treatment with disease-modifying antirheumatic drugs (DMARDs) on all-cause mortality in patients with rheumatoid arthritis and prevalent interstitial lung disease (RA-ILD). METHODS: Patients with RA-ILD were selected from the biologics register Rheumatoid Arthritis: Observation of Biologic Therapy (RABBIT). Using time-varying Cox regression, the association between clinical measures and mortality was investigated. The impact of DMARDs was analysed by (1) Cox regression considering cumulative exposure (ie, treatment months divided by total months) and (2) time-varying Cox regression as main approach (treatment exposures at monthly level). RESULTS: Out of 15 566 participants, 381 were identified as RA-ILD cases with 1258 person-years of observation and 2.6 years median length of follow-up. Ninety-seven patients (25.5%) died and 34 (35.1%) of these were not receiving DMARD therapy at the time of death. Higher inflammatory biomarkers but not swollen and tender joint count were significantly associated with mortality. Compared with tumour necrosis factor inhibitors (TNFi), non-TNFi biologic DMARDs (bDMARDs) exhibited adjusted HRs (aHRs) for mortality below 1, lacking statistical significance. This finding was stable in various sensitivity analyses. Joint aHR for non-TNFi biologics and JAKi versus TNFi was 0.56 (95% CI 0.33 to 0.97). Receiving no DMARD treatment was associated with a twofold higher mortality risk compared with receiving any DMARD treatment, aHR 2.03 (95% CI 1.23 to 3.35). CONCLUSIONS: Inflammatory biomarkers and absence of DMARD treatment were associated with increased risk of mortality in patients with RA-ILD. Non-TNFi bDMARDs may confer enhanced therapeutic benefits in patients with RA-ILD.

Pregnancy in women with psoriatic arthritis: A systematic literature review of disease activity and adverse pregnancy outcomes.

BACKGROUND: There is limited robust evidence on the course of pregnancy and its outcomes in women with psoriatic arthritis (PsA) on which to base recommendations for the management of these patients. OBJECTIVE: The primary objective was to review available data on (I) disease activity during pregnancy and on (II) adverse pregnancy outcomes (APO) in women with PsA. Secondly, neonatal outcomes and treatment of the rheumatic disease were investigated. METHODS: Systematic literature search within the databases Pubmed and Embase until 30 Nov 2020 was performed. Additionally, reference lists of included studies and of review articles revealed by the search were screened. All full text articles identified and published in English language were systematically evaluated by two reviewers. All studies that reported on one of the primary outcomes and included at least five pregnancies in women with PsA were considered. RESULTS: The review of 734 search results revealed 13 eligible publications reporting on a total of 2,332 pregnancies in women with PsA. Nine studies reported on PsA activity and showed an increase or worsening of disease activity after delivery compared to the pregnancy period. APOs were reported by nine studies. Adjusted analyses of APOs did not show an increased risk for gestational diabetes, small for gestational age and low birth weight in PsA patients in relation to the respective comparator groups. However, there were signals for a higher pre-eclampsia, elective caesarean section and preterm birth risk in PsA pregnancies. Meta-analysis was not performed due to study heterogeneity. DISCUSSION: This review showed a postpartum deterioration of disease activity in women with PsA and no risk elevation for gestational diabetes, small for gestational age and low birth weight. A higher risk for pre-eclampsia, elective caesarean section and preterm birth in PsA pregnancies cannot be ruled out. Differences in the studies investigated limit overall summary statements on disease activity and APOs in women with PsA. Harmonization of study approaches, instruments and outcome reporting is crucial to ensure informed counselling of patients with PsA before, during and after pregnancy that is based on robust data. PROSPERO REGISTRATION NUMBER: CRD42020162242.

Osteoimmunology of tumor necrosis factor-alpha, IL-6, and RANTES/CCL5: a review of known and poorly understood inflammatory patterns in osteonecrosis.

BACKGROUND: The immune and bone systems are closely linked via cytokine cross-talk. This interdisciplinary field of research is referred to as osteoimmunology and pertains to inflammatory and osteoarticular diseases that feature the primary expression of tumor necrosis factor-alpha (TNF-α) and IL-6. OBJECTIVE: Are there bone resorptive processes wherein chronic inflammatory conditions are not linked to TNF-α and IL-6 expression, but rather to the expression of other cytokines? MATERIALS AND METHODS: A comprehensive literature search was performed in PubMed Central. DISCUSSION: Although all diseases with cytokines involved in bone resorption (TNF-α and IL-6) are at the forefront of destructive inflammatory processes, there is one exception in the literature: fatty oxide osteoporosis/osteolysis in the jawbone (FDOJ), which is associated with significant bone softening. However, it should be noted that TNF-α and IL-6 fall below the levels found in a healthy jawbone in this condition. Another conspicuous finding is that there is a nearly 35-fold overexpression of the chemokine RANTES/CCL5 (R/C) in all FDOJ cases studied thus far in the literature. CONCLUSION: FDOJ appears to represent a unique cytokine and inflammatory pattern from osteolysis in the body. R/C can be defined as the dominant carrier of a "maxillomandibular osteoimmunology".

The vitamin D receptor and the etiology of RANTES/CCL-expressive fatty-degenerative osteolysis of the jawbone: an interface between osteoimmunology and bone metabolism.

BACKGROUND: Recent research on vitamin D indicates that our current understanding of the factors leading to chronic inflammation should be revised. One of the key mechanisms by which microbial immunosuppression occurs is the suppression of one of the most common endogenous cell nucleus receptors: the vitamin D receptor (VDR). Autoimmune diseases may be correlated with VDR deactivation (VDR-deac) which occurs when the receptor is no longer able to transcribe antimicrobial agents. Excess 1,25-dihydroxyvitamin D (1,25D) is not converted to 25-hydroxyvitamin D (25D); thus, high 1,25D levels may be accompanied by low 25D values. PATIENTS AND METHODS: Since 1,25D promotes osteoclast activity and may thereby cause osteoporosis, fatty-degenerative osteolysis of the jaw (FDOJ), as described by our team, may also be associated with VDR-deac. In 43 patients, vitamin D conversion, immune system function and the quality of bone resorption and formation in the jawbone were related factors that may enhance chronic inflammatory processes. Here, we examine the relationship between immunology and bone metabolism among 43 FDOJ patients and those with immune system diseases (ISDs). RESULTS: We provide a link between FDOJ, RANTES/CCL5 overexpression and VDR-deac. CONCLUSION: The clinical data demonstrate the interaction between VDR-deac and proinflammatory RANTES/CCL5 overexpression in FDOJ patients.

Proteome survey reveals modularity of the yeast cell machinery.

Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling.

Functional organization of the yeast proteome by systematic analysis of protein complexes.

Most cellular processes are carried out by multiprotein complexes. The identification and analysis of their components provides insight into how the ensemble of expressed proteins (proteome) is organized into functional units. We used tandem-affinity purification (TAP) and mass spectrometry in a large-scale approach to characterize multiprotein complexes in Saccharomyces cerevisiae. We processed 1,739 genes, including 1,143 human orthologues of relevance to human biology, and purified 589 protein assemblies. Bioinformatic analysis of these assemblies defined 232 distinct multiprotein complexes and proposed new cellular roles for 344 proteins, including 231 proteins with no previous functional annotation. Comparison of yeast and human complexes showed that conservation across species extends from single proteins to their molecular environment. Our analysis provides an outline of the eukaryotic proteome as a network of protein complexes at a level of organization beyond binary interactions. This higher-order map contains fundamental biological information and offers the context for a more reasoned and informed approach to drug discovery.