Towards development of core domain sets for short term and long term studies of calcium pyrophosphate crystal deposition (CPPD) disease: A framework paper by the OMERACT CPPD working group

IntroductionAlthough calcium pyrophosphate deposition (CPPD) is common, there are no published outcome domains or validated measurement instruments for CPPD studies. In this paper, we describe the framework for development of the Outcome Measures in Rheumatology (OMERACT) CPPD Core Domain Sets.MethodsThe OMERACT CPPD working group performed a scoping literature review and qualitative interview study. Generated outcomes were presented at the 2020 OMERACT CPPD virtual Special Interest Group (SIG) meeting with discussion focused on whether different core domain sets should be developed for different calcium pyrophosphate deposition (CPPD) clinical presentations and how the future CPPD Core Domain Set may overlap with already established osteoarthritis (OA) domains. These discussions informed development of a future work plan for development of the OMERACT CPPD Core Domain Sets.FindingsDomains identified from a scoping review of 112 studies and a qualitative interview study of 36 people (28 patients with CPPD, 7 health care professionals, one stakeholder) were mapped to core areas of OMERACT Filter 2.1. The majority of SIG participants agreed there was need to develop separate core domain sets for “short term” and “long term” studies of CPPD. Although CPPD + OA is common and core domain sets for OA have been established, participants agreed that existing OA core domain sets should not influence the development of OMERACT core domain sets for CPPD. Prioritization exercises (using Delphi methodology) will consider 40 potential domains for short term studies of CPPD and 47 potential domains for long term studies of CPPD.ConclusionSeparate OMERACT CPPD Core Domain Sets will be developed for “short term” studies for an individual flare of acute CPP crystal arthritis and for “long term” studies that may include participants with any clinical presentation of CPPD (acute CPP crystal arthritis, chronic CPP crystal inflammatory arthritis, and/or CPPD + OA).     

Calcium pyrophosphate crystal formation in aqueous solutions

Pseudogout is characterized by the deposition of calcium pyrophosphate dihydrate, triclinic [CPPD(T)] and calcium pyrophosphate dihydrate, monoclinic [CPPD(M)] crystals in articular connective tissues. We studied aqueous solutions over a range of calcium chloride/sodium pyrophosphate concentrations to determine the ionic conditions under which these particular salts form. At 37 degrees C, CPPD(T) forms when [PPi]t greater than or equal to 10(-4), while formation of CPPD(M) occurs at 10(-3) M < [PPi]t less than or equal to 10(-2) M. When [Na+]t > 120 mM, calcium disodium pyrophosphates precipitate. With 1 mM Mg++, CPPD(M) forms at [PPi]t > 10(-3) M, mixed with a calcium magnesium pyrophosphate at [PPi]t greater than or equal to 10(-2) M. We conclude that CPPD(T) and CPPD(M) crystals form in a restricted ratio and range of [Ca++]t and [PPi]t and that other ions, particularly Mg++ and Na+, affect the nature of the crystal products formed.     

Correcting Anemia in Heart Failure: The Efficacy and Safety of Erythropoiesis-Stimulating Agents

BackgroundRandomized controlled trials (RCTs) evaluating the efficacy and safety of erythropoiesis-stimulating agents (ESAs), including erythropoietin and darbepoetin, among patients with chronic heart failure (CHF) and anemia have yielded heterogeneous results, and important safety questions remain unanswered. We therefore undertook a meta-analysis to examine the effects of ESAs in this population.Methods and ResultsWe systematically searched EMBASE, Medline, the Cochrane Library, ClinicalTrials.gov, and relevant bibliographies to identify all relevant RCTs. Data were aggregated using random-effects models. We identified 9 RCTs (n = 747 patients). Compared with control, ESAs were associated with a significant reduction in CHF-related hospitalizations (odds ratio [OR] = 0.41; 95% confidence interval [CI] = 0.24-0.69). The effect of ESAs on mortality was inconclusive (OR = 0.60; 95% CI = 0.32-1.11). ESAs were associated with improved quality of life and left ventricular ejection fraction, lower brain-natriuretic peptide levels, and improved exercise tolerance test performance. There was no evidence of an increase in the incidence of adverse events among patients randomized to ESAs (OR = 0.86; 95% CI = 0.51-1.42).ConclusionsIn patients with CHF and anemia, ESAs are associated with a decrease in CHF-related hospitalizations and improved quality of life and exercise tolerance. However, RCTs completed to date have involved a small number of patients, and available mortality data are inconclusive.     

Experience and impact of crystal pyrophosphate deposition (CPPD) from a patient and caregiver perspective: A qualitative exploration from the OMERACT CPPD working group

ObjectiveTo explore the lived experience of people with calcium pyrophosphate deposition (CPPD) disease and the impact of this condition on their daily lives.MethodsPatients with CPPD and their caregivers were invited to take part in a one-to-one (patient only) or paired (patient and caregiver) semi-structured interview. Interviews covered patients’ diagnosis and treatment experiences, and the impact of CPPD on their daily lives. Transcribed interviews were analysed using inductive thematic analysis.Results28 patient interviews, six of which included a caregiver, were conducted across five countries. Acute CPP crystal arthritis flares resulted in temporary but profound disability for most patients, disrupting their ability to go about day-to-day activities, and they sought immediate medical attention. CPPD+OA and chronic CPP crystal inflammatory arthritis presented patients with longer term limitations in daily lives. Patients and their caregivers described these disruptions and limitations, which included a reduced ability or inability to complete household and self-care tasks, exercise, socialise, work and drive. They also described how arthritis pain and resulting limitations adversely impacted upon patients’ psychological wellbeing. Delays in referral to specialists and diagnostic uncertainty were described by many. Lack of appropriate treatment or access to treatments only upon worsening of symptoms impacted upon the length of time some patients spent in pain and with functional limitations.ConclusionThis study is the first to demonstrate the wide-ranging impact of CPPD, and highlights the need for improved diagnosis, physician training, as well as greater emphasis upon finding targeted therapies to specifically treat CPPD.     

The effect of calcium and magnesium ions on calcium pyrophosphate crystal formation in aqueous solutions

Calcium pyrophosphate crystal formation has been associated clinically with hypercalcemic states (hyperparathyroidism) and hypomagnesemia. We studied aqueous solutions at pH 7.4, 37 degrees C, [Na+] = 140 nM over a range of calcium chloride/magnesium chloride/sodium pyrophosphate concentrations to determine the effect of calcium and magnesium ions on crystal formation. We found that CPPD(T) and CPPD(M) could form under different ionic conditions. Low [Mg++] and [PPi] favoured CPPD(T) whereas higher [Mg++] and [PPi] favoured CPPD(M). At [Mg++] = 1.0 mM a calcium magnesium pyrophosphate crystal phase designated CMPP2 formed. As [Mg++] affects the crystal phase formed more than equimolar [Ca++], we conclude that ionic magnesium deficiency may be a clinically important determinant in calcium pyrophosphate dihydrate crystal formation.     

Review: Outcome measures in calcium pyrophosphate deposition

This review highlights outcomes for patients with calcium pyrophosphate deposition (CPPD) reported in prior studies and underscores challenges to assessing outcomes of this condition. Prior clinical studies of interventions for CPPD focused on joint damage and calcification on imaging tests, joint pain, swelling, and inflammatory biomarkers. Qualitative interviews with patients with CPPD and healthcare providers additionally identified flares, overall function, and use of analgesic medications as important outcomes. Imaging evidence of joint damage and calcification is likely to be outcomes in future clinical studies of CPPD, though reliability and sensitivity to change in CPPD require further testing for several imaging modalities. Challenges to outcome measurement in CPPD include questions of attribution of signs and symptoms to CPPD versus co-existing forms of arthritis, lack of therapies to prevent or dissolve calcium pyrophosphate crystal deposition, absence of validated patient- or physician-reported CPPD outcome measures, and scarcity of large cohorts in which to study outcomes of different clinical presentations of CPPD.     

Genetics and Mechanisms of Crystal Deposition in Calcium Pyrophosphate Deposition Disease

Calcium pyrophosphate deposition (CPPD) disease (common in older adults) can be asymptomatic, associated with osteoarthritis, or can present as acute/chronic inflammatory arthritis. Due to the phenotypic complexity of CPPD, the European League Against Rheumatism (EULAR) recently made recommendations on terminology, diagnosis, and management based on available research evidence and expert consensus. There are no disease-modifying treatments for CPPD disease, and therapy remains nonspecific with the use of anti-inflammatory and analgesic drugs. For years, it has been known that inorganic phosphate and pyrophosphate regulate the formation of CPP or hydroxyapatite crystals. The discovery of ANKH (human homologue of progressive ankylosis) mutations in familial CPPD disease confirmed the importance of phosphate/pyrophosphate homeostasis in CPPD, with ANKH being a regulator of inorganic pyrophosphate transport. Despite progress in our understanding of the function of ANKH, much remains to be investigated. This review summarizes the genetic basis of this disease and focuses on the challenges of research in this area.     

Pyrophosphate, phosphate ion interaction: effects on calcium pyrophosphate and calcium hydroxyapatite crystal formation in aqueous solutions

The relationship between ambient ionic conditions that favor pyrophosphate (PPi) versus phosphate (Pi) biomineralization is important to understanding the pathogenesis of chondrocalcinosis. We studied aqueous solutions at pH 7.4, 37 degrees C, [Na+] = 140 mM, [Mg+ +] = 0.5 mM, [Ca+ +] = 1.0 or 1.5 mM over a range of pyrophosphate and phosphate concentrations to determine the effect of different ambient concentrations and ratios of Pi/PPi on calcium pyrophosphate dihydrate (CPPD) and calcium hydroxyapatite (HA) crystal formation. We found that the Pi/PPi ratio is an extremely important determinant of the crystal product formed. At low [Pi], CPPD crystal formation is partially inhibited by Pi; at higher [Pi], calcium pyrophosphate, calcium phosphate and calcium pyrophosphate-phosphate complexes amorphous to x-ray diffraction are formed; whereas at still higher [Pi], HA crystal formation partially inhibited by PPi. We conclude that CPPD forms when the ratio [Pi]/[PPi] less than 3 and HA forms when [Pi]/[PPi] greater than 100.     

Therapy for CPPD: Options and Evidence

Purpose of Review

Current evidence and accumulated experience for the management of calcium pyrophosphate deposition disease (CPPD) are presented.

Recent Findings

Contrary to other rheumatic inflammatory conditions that account for high interest and growing research, advances in treating CPPD are still very limited and mostly derive from those achieved in gout.

Summary

Once formed, calcium pyrophosphate crystals cannot be dissolved; therefore, management relies on the control of crystal-derived inflammation. Besides classical agents—such as colchicine, glucocorticoids, or NSAIDs—the use of targeted therapies, mostly against interleukin-1, has provided a relevant relief for refractory CPPD patients in recent years. Meanwhile, former enthusiasm about conventional disease-modifying agents such as methotrexate is currently controversial.

     

Risk of herpes zoster associated with biological therapies for psoriasis and psoriatic arthritis: A systematic review and meta-analysis

Background:Biological therapy is effective for the treatment of psoriasis and psoriatic arthritis; however, adverse effects related to immunosuppression, such as viral infections, have been reported. Amongst these infections, herpes zoster (HZ) is common.Objective:To evaluate the risk of HZ in psoriasis and psoriatic arthritis patients treated with biological therapy.Data sources:A comprehensive literature search of PubMed, Embase, and Web of Science was performed using certain keywords until October 9, 2020. Nine studies were included after a detailed assessment.Study eligibility criteria:The eligibility criteria included randomized controlled trials (RCTs) and observational studies of patients with psoriasis or psoriatic arthritis treated with biological therapies; compared with non-biological therapies, non-biological systemic therapies, or controls; with the incidence of HZ reported in case and control groups. The Cochrane risk of bias tool and Newcastle-Ottawa scale were used to assess the quality of the RCTs and observational studies, respectively. Data were extracted from 9 eligible studies and then analyzed using Stata software (Version 12.0).Results:The risk of HZ in biological therapies was higher than that in non-biological (odds ratios [OR]: 1.48; 95% confidence interval [CI]: 1.18–1.86; I² = 0%) and non-biological systemic (OR: 1.32; 95% CI: 1.02–1.71; I² = 0%) therapies. Furthermore, the risk of HZ associated with tumor necrosis factor-α inhibitors increased significantly (OR: 1.50; 95% CI: 1.11–2.02; I² = 0%). Notably, infliximab (OR: 2.43; 95% CI: 1.31–4.50; I² = 0%) and etanercept (OR: 1.65; 95% CI: 1.07–2.56; I² = 0%) increased the risk of HZ, while adalimumab (OR: 1.21; 95% CI: 0.64–2.30; I² = 0%), ustekinumab (OR: 2.20; 95% CI: 0.89–5.44; I² = 0%), alefacept (OR: 1.46; 95% CI: 0.20–10.47; I² = 0%), and efalizumab (OR: 1.58; 95% CI: 0.22–11.34; I² = 0%) did not.Limitations:Few RCTs have reported HZ incidents; thus, our results require confirmation via large-scale RCTs.Conclusions and implications of key findings:Biological therapies, especially tumor necrosis factor-α inhibitors, may lead to the risk of HZ in psoriasis and psoriatic arthritis patients. Amongst these agents, infliximab and etanercept have been shown to significantly increase the risk of HZ. Additionally, younger age and female sex may be risk factors.Systematic review registration number:INPLASY202110027.     

Comparative effectiveness of biologics for the management of rheumatoid arthritis: systematic review and network meta-analysis

Our aim was to establish the comparative effectiveness of rheumatoid arthritis (RA) biologics, using a systematic review and network meta-analysis. The systematic review used randomized controlled trials (RCTs) in adults with RA who failed treatment with conventional disease-modifying agents for rheumatoid disease (cDMARDs). We compared the effectiveness of abatacept, adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, and rituximab to tocilizumab, a recent biologic with a different mechanism of action (anti-IL-6 receptor). A network meta-analysis (NMA) included the indirect and direct evidence previously selected. In total, 207 articles were included describing 68 RCTs. The NMA showed that tocilizumab monotherapy was superior to standard care (ACR20, OR 13.27, 95 % CrI [3.958, 43.98]; ACR50, 17.45 [10.18, 31.24]; ACR70, 37.77 [7.226, 216.3]; EULAR, 10.42 [1.963, 54.8]); and methotrexate (MTX; ACR50, OR 5.44 [4.142, 7.238]; ACR70, 7.364 [1.4, 30.83]; EULAR, 4.226 [1.184, 15.58]) at 26 weeks. Similarly, the combination of tocilizumab + MTX was significantly better than standard care/placebo and MTX alone for ACR20, ACR50, ACR70, and EULAR at 26 weeks (OR 18.63 [5.32, 66.81]; 24.27 [14.5, 41.91]; 46.13 [10.08, 277]; 14.23 [2.493, 84.02]; 4.169 [2.267, 7.871]; 5.44 [4.142, 7.238]; 8.731 [4.203, 19.29]; 7.306 [4.393, 13.04], respectively). At 52 weeks, compared to MTX alone, tocilizumab + MTX was significantly better for ACR20 and ACR50 response. Few significant differences were found between tocilizumab (alone or in combination) and any other biologics. Results must be considered in context with the limitations of the available evidence. This NMA suggests that tocilizumab was superior to cDMARDs and as effective as other biologics for RA.     

A mini systematic review of prognostic factors in elderly patients with tuberculosis

BackgroundWhile advanced age has been suggested as a prognostic factor in patients with tuberculosis, the characteristics associated with a poor outcome in elderly patients have remained unclear. The aim of this systematic review was to describe the risk factors for a poor outcome in elderly patients with tuberculosis.MethodsWe identified 1255 studies published between 1919 and 2017 from the PubMed database by using combinations of the keywords “tuberculosis [Title/Abstract]” and “elderly [Title/Abstract]”. Full texts of the studies that met the inclusion criteria were further evaluated by two independent investigators.Resultseven retrospective cohort studies were included in this systematic review. More advanced age, comorbidities, and nutritional status were likely to be prognostic factors in Taiwan (aging country) and Japan (super-aged country), while human immunodeficiency virus infection and severe tuberculosis were associated with a poor outcome in low-income countries. Two studies from Taiwan investigated the prognostic factors of tuberculosis-specific death and non-tuberculosis-specific death separately, but no significant differences were found in the factors between the two types of death.ConclusionsThe prognostic factors of tuberculosis in elderly patients varied according to the income levels of the countries. The factors in Taiwan and Japan were mainly associated with host factors, irrespective of the cause of death, which may reflect senile deterioration due to old age.     

CRYSTAL SHEDDING IN SEPTIC ARTHRITIS: CASE REPORTS AND IN VIVO EVIDENCE IN AN ANIMAL MODEL

Abstract Two cases of coexisting septic and crystalline joint disease are reported. In one patient polyarticular septic artaritis occurred simultaneously with gout and pseudogout. In a second patient septic arthritis preceded the appearance of calcium pyrophosphate dihydrate (CPPD) crystals in the joint fluid, supporting an earlier postulate that lysosomal enzymes released during sepsis lead to shedding of crystals from cartilage and synovium into the joint space. This sequence was demonstrated in a rat air pouch model of synovium, in which CPPD crystals embedded in facsimile synovial tissue were released after injection of pyogenic bacteria. Coexisting septic arthritis should always be considered when crystals are identified in inflamed joints, particularly in elderly patients with concurrent infections.     

Febrile presentation of calcium pyrophosphate dihydrate deposition disease

Three patients were found to have calcium pyrophosphate dihydrate deposition disease (CPPD) as the cause of prolonged fever and elevated sedimentation rate. All responded to treatment. CPPD should be considered in evaluating patients with fever and high sedimentation rate.     

Pathogenesis of calcium pyrophosphate deposition disease

Calcium pyrophosphate deposition disease is defined by the presence of calcium pyrophosphate (CPP) crystals in articular cartilage and is the fourth most common type of arthritis in adults. Despite its high prevalence, the etiology of CPPD disease remains unclear and no specific therapies currently exist. It has been known for several decades that abnormalities of cartilage pyrophosphate metabolism are common in patients with CPPD disease, and this classic work will be reviewed here. Recent studies of rare familial forms of CPPD disease have provided additional novel information about its pathophysiology. This work suggests that CPPD disease occurs through at least two unique and potentially intertwined biomolecular pathways. We are hopeful that a detailed understanding of the components and regulation of these pathways will lead to improved therapies for this common disease.     

A systematic review and meta-analysis of randomized controlled trials comparing laparoscopic and open liver resection

Background/purposeThe dissemination of laparoscopic liver resection (LLR) has been based on non-randomized studies and reviews of these. Aim of this study was to evaluate if the randomized evidence comparing LLR to open liver resection (OLR) supports these findings.MethodsA prospectively registered (reviewregistry866) systematic review and meta-analysis following Cochrane and PRISMA guidelines comparing LLR to OLR for benign and malignant diseases was performed via Medline, Web of Science, CENTRAL up to 31.12.2020. The main outcome was postoperative complications. Risk of bias was assessed with the Cochrane Risk of Bias tool 2.0, certainty of evidence was assessed using the GRADE approach.ResultsThe search yielded 2080 results. 13 RCTs assessing mostly minor liver resections with 1457 patients were included. There were reduced odds of experiencing any complication (Odds ratio (OR) [95% confidence interval (CI)]: 0·42 [0·30, 0·58]) and severe complications (OR[CI]: 0·51 [0·31, 0·84]) for patients undergoing LLR. LOS was shorter (Mean difference (MD) [CI]: −2·90 [-3·88, −1·92] days), blood loss was lower (MD: [CI]: −115·41 [-146·08, −84·75] ml), and functional recovery was better for LLR. All other outcomes showed no significant differences.ConclusionsLLR shows significant postoperative benefits. RCTs assessing long-term outcomes and major resections are needed.     

Ferrous [Fe++] but not ferric [Fe] ions inhibit de novo formation of calcium pyrophosphate dihydrate crystals: possible relationships to chondrocalcinosis and hemochromatosis

To determine the physical-chemical effects of [Fe++] and [Fe ] on calcium pyrophosphate dihydrate (CPPD) crystal formation de novo, we studied CPPD crystal formation in an established model aqueous solution mixture system using physiological concentrations of Na+, Mg++, Ca++, C1-. We found that [Fe++] greater than 1 microM or [Fe ] greater than or equal to 100 microM inhibits CPPD crystal formation under conditions of [Ca++] = 1.5 mM, [Pi] = 0.1 mM, and [PPi] = 0.1 mM that simulate CPPD formation in vivo. These experiments suggest that at biological concentrations, Fe++ acts to inhibit CPPD formation but that [Fe++] depletion therapy by removal of inhibition effects may facilitate CPPD crystal formation in articular tissues.     

Interventions that enhance health-professional contact with parents and infants to improve child development and social and emotional wellbeing in the early years in high-income countries: a systematic review

BackgroundExperiences in the first 1000 days of life have a crucial influence on child development and health. Universal health services provide support for families during this time, but new unassessed components are often added. We systematically reviewed the evidence for interventions in high-income countries designed to improve child development by enhancing health professional contact with parents in the very early years.MethodsWe searched Cochrane Central Register of Controlled Trials, Medline, Embase, CINAHL, PsycINFO, Web of Science, Scopus, ASSIA, LiLACS, Sociological Abstracts, Social Services Abstract, OpenGrey, ClinicalTrials.gov, UK Clinical Trials Gateway, and the WHO International Clinical Trials Registry Platform for studies published in any language between Jan 1, 1996, and Dec 17, 2014, using subject headings and key words with the following search structure: [health OR parenting professionals OR known programme names] AND [child development OR emotional/behavioural OR language OR cognitive outcomes]. We hand searched eight journals and 47 programme or organisation websites. We included randomised controlled trials (RCTs) that examined professional interventions designed to augment existing universal health-care provision from the antenatal period to 2 years post partum. Primary outcomes were motor, cognitive, and language development, and social and emotional wellbeing, measured to 3 years of age. Results were reported by narrative synthesis, because of heterogeneity in intervention design and outcome measurement.FindingsOf 12 473 studies identified, 21 RCTs met eligibility criteria. 15 had a high or unclear risk of bias as judged by Cochrane criteria. There was limited evidence for intervention effectiveness: some positive effects were seen in one of five studies for motor development, four of ten for language development, four of seven for cognitive development, and five of 18 for social and emotional wellbeing. However, most positive effects were in studies at high or unclear risk of bias, within-study effects were inconsistent, and negative effects were also seen. Intervention content and intensity varied greatly, but this was not associated with effectiveness. The quality of evidence overall was low as judged by GRADE criteria.InterpretationEvidence that interventions to enhance universal health services up to 2 years postpartum are effective for improving child development is weak. There is an urgent need for more robust assessment of existing interventions, and to develop and evaluate novel interventions to enhance the universal offer.FundingPublic Health Wales.     

Comparative efficacy and safety of biosimilar adalimumab and originator adalimumab in combination with methotrexate in patients with active rheumatoid arthritis: a Bayesian network meta-analysis of randomized controlled trials

We aimed to assess the relative efficacy and safety of biosimilar adalimumab and originator adalimumab plus methotrexate (MTX) compared to those of placebo plus MTX in patients with active rheumatoid arthritis (RA) who showed an inadequate response to MTX. We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) examining the efficacy and safety of biosimilar + MTX and adalimumab + MTX versus placebo + MTX (MTX group) in patients with active RA despite treatment with MTX. A total of eight RCTs involving 2543 patients met the inclusion criteria. The ACR20 response rate was significantly higher in the biosimilar + MTX (odds ratio [OR] 2.91, 95% credible interval [CrI] 1.57–5.74) and adalimumab + MTX (OR 2.80, 95% CrI 1.81–4.46) groups than in the MTX group, with no difference in the ACR20 response rate between the biosimilar + MTX and adalimumab + MTX groups. Biosimilar + MTX had the highest probability of being the best treatment in terms of the ACR20 response rate (surface under the cumulative ranking curve [SUCRA]?=?0.7896), followed by adalimumab + MTX (SUCRA?=?0.7082) and MTX (SUCRA?=?0.0022). The ACR50 and ACR70 response rates showed a distribution pattern similar to that of the ACR20 response rate. Safety based on the number of serious adverse events did not differ significantly among the three interventions in the follow-up period of 12 to 24 weeks. Biosimilar and originator adalimumab, in combination with MTX, represent an effective intervention for active RA despite treatment with MTX. No significant difference was found between biosimilar and originator adalimumab in terms of efficacy and safety. However, follow-up in RCTs is short and not all safety outcomes can be assessed in RCTs. Thus, additional long-term evaluations are needed.