[Diastolic dysfunction of ventricles in patients with calcium pyrophosphate crystal deposition disease while receiving anti-inflammatory therapy].

BACKGROUND: Calcium pyrophosphate crystal deposition disease (CPPD) may be associated with developing of diastolic dysfunction (DD). AIM: To determine the variability of echocardiographic parameters in patients with CPPD receiving anti-inflammatory therapy. MATERIALS AND METHODS: Twenty six patients with CPPD and osteoarthritis (OA) from 18 to 65 years old were included in the case-control study. All patients underwent echocardiography, laboratory parameters at baseline and after 6 months. Patients with CPPD received methotrexate 15 mg per week or hydroxychloroquine 200 mg once a day, or colchicine 1 mg per day. Diastolic function according to echocardiography was assessed. RESULTS: Diastolic dysfunction was detected in 19 patients: in 11 (42%) patients with CPPD and 8 (31%) patients with OA (p=0.39). The baseline serum CRP level was higher in the CPPD group (p=0.03), no differences were found for other indicators. Twenty-two patients with CPPD and 19 patients with OA completed the study. In patients with OA, there were no significant changes in indicators reflecting the diastolic function of ventricles. CONCLUSION: CPPD therapy with colchicine, hydroxychloroquine and methotrexate has a positive effect on indicators of diastolic ventricular function.

Histone Deacetylase Inhibitors Downregulate Calcium Pyrophosphate Crystal Formation in Human Articular Chondrocytes.

Calcium pyrophosphate (CPP) deposition disease (CPPD) is a form of CPP crystal-induced arthritis. A high concentration of extracellular pyrophosphate (ePPi) in synovial fluid is positively correlated with the formation of CPP crystals, and ePPi can be upregulated by ankylosis human (ANKH) and ectonucleotide pyrophosphatase 1 (ENPP1) and downregulated by tissue non-specific alkaline phosphatase (TNAP). However, there is currently no drug that eliminates CPP crystals. We explored the effects of the histone deacetylase (HDAC) inhibitors (HDACis) trichostatin A (TSA) and vorinostat (SAHA) on CPP formation. Transforming growth factor (TGF)-ß1-treated human primary cultured articular chondrocytes (HC-a cells) were used to increase ePPi and CPP formation, which were determined by pyrophosphate assay and CPP crystal staining assay, respectively. Artificial substrates thymidine 5'-monophosphate p-nitrophenyl ester (p-NpTMP) and p-nitrophenyl phosphate (p-NPP) were used to estimate ENPP1 and TNAP activities, respectively. The HDACis TSA and SAHA significantly reduced mRNA and protein expressions of ANKH and ENPP1 but increased TNAP expression in a dose-dependent manner in HC-a cells. Further results demonstrated that TSA and SAHA decreased ENPP1 activity, increased TNAP activity, and limited levels of ePPi and CPP. As expected, both TSA and SAHA significantly increased the acetylation of histones 3 and 4 but failed to block Smad-2 phosphorylation induced by TGF-ß1. These results suggest that HDACis prevented the formation of CPP by regulating ANKH, ENPP1, and TNAP expressions and can possibly be developed as a potential drug to treat or prevent CPPD.

The role of Interleukin-1 receptor antagonist as a treatment option in calcium pyrophosphate crystal deposition disease.

Calcium Pyrophosphate Crystal Deposition (CPPD) disease is characterized by the deposition of calcium pyrophosphate crystals in the cartilage. In most cases, it can manifest as a subclinical condition named chondrocalcinosis, often revealed by joint x-ray examination. In other cases, deposition can cause flares of arthritis, known as acute CPP crystal arthritis. In the last few years, many pathogenic pathways have been discovered. Interleukin-1 (IL-1) plays a key role in the pathogenesis of CPPD disease, both as a mediator of inflammatory response to crystals and as a promoter of damage to articular cartilage. In this review, we investigated the role of IL-1R inhibitor, such as Anakinra, as an alternative to the various therapeutic strategies for CPPD disease, especially among patients resistant to traditional treatment with NSAIDs, corticosteroids and colchicine.

Biologics in the treatment of calcium pyrophosphate deposition disease: a systematic literature review.

The main aim of this systematic literature review (SLR) was to summarise the evidence in the use of biological therapies in calcium pyrophosphate deposition disease (CPPD). We performed a SLR using PubMed, Embase and Cochrane databases. Only studies reporting the efficacy of biologics in CPPD were selected. The search resulted in 83 articles; 11 were further evaluated in the SLR. Seventy-six patients were included: 2 received infliximab, whereas 74 anakinra. Anakinra was used in refractory disease (85.1%) or in patients with contraindications to standard treatments (23.0%). Clinical response to anakinra was observed in 80.6% of patients with acute and 42.9% of those with chronic CPPD. Short-term treatment was well tolerated and adverse events were reported in 4.1% of the cases. This review provides evidence in favour of the use of anakinra as a therapeutic option in patients with CPPD, especially in acute refractory CPPD or when standard treatments are contraindicated.

Two cases of pressure ulcers related to acute calcium pyrophosphate crystal arthritis: A new concept of "disease-specific unexpected external forces".

Sudden-onset immobilisation generates unexpected external forces over bony prominences and is a potential cause of pressure ulcers. Here, we report two cases of deep pressure ulcers in patients with acute monoarthritis as a result of calcium pyrophosphate (CPP) crystal deposition (pseudogout). The patients were women in their 80 who could perform activities of daily living by themselves. They developed pressure ulcers while living in their own home. Because acute CPP crystal arthritis is known to develop in relatively healthy elderly patients, patients and caregivers do not expect sudden-onset immobilisation. In addition, larger joints are preferentially involved in acute CPP crystal arthritis, leading to the inability of patients to change positions themselves. Therefore, acute CPP crystal arthritis should be recognised as a potential causal disease for pressure ulcers. This case report further highlights a new concept of "disease-specific unexpected external force", which is beneficial for the prevention of pressure ulcers.

Inhibition of nucleotide pyrophosphatase/phosphodiesterase 1: implications for developing a calcium pyrophosphate deposition disease modifying drug.

Objectives: Calcium pyrophosphate deposition (CPPD) is associated with osteoarthritis and is the cause of a common inflammatory articular disease. Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (eNPP1) is the major ecto-pyrophosphatase in chondrocytes and cartilage-derived matrix vesicles (MVs). Thus, eNPP1 is a principle contributor to extracellular pyrophosphate levels and a potential target for interventions aimed at preventing CPPD. Recently, we synthesized and described a novel eNPP1-specific inhibitor, SK4A, and we set out to evaluate whether this inhibitor attenuates nucleotide pyrophosphatase activity in human OA cartilage. Methods: Cartilage tissue, chondrocytes and cartilage-derived MVs were obtained from donors with OA undergoing arthroplasty. The effect of SK4A on cell viability was assayed by the XTT method. eNPP1 expression was evaluated by western blot. Nucleotide pyrophosphatase activity was measured by a colorimetric assay and by HPLC analysis of adenosine triphosphate (ATP) levels. ATP-induced calcium deposition in cultured chondrocytes was visualized and quantified with Alizarin red S staining. Results: OA chondrocytes expressed eNPP1 in early passages, but this expression was subsequently lost upon further passaging. Similarly, significant nucleotide pyrophosphatase activity was only detected in early-passage chondrocytes. The eNPP1 inhibitor, SK4A, was not toxic to chondrocytes and stable in culture medium and human plasma. SK4A effectively inhibited nucleotide pyrophosphatase activity in whole cartilage tissue, in chondrocytes and in cartilage-derived MVs and reduced ATP-induced CPPD. Conclusion: Nucleotide analogues such as SK4A may be developed as potent and specific inhibitors of eNPP1 for the purpose of lowering extracellular pyrophosphate levels in human cartilage with the aim of preventing and treating CPPD disease.

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. 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.

Mineral and Bone Disorder in Chronic Kidney Disease: A Case Report from Vietnam.

We report a case of calcium pyrophosphate dihydrate deposition disease (CPDD) involving a patient on maintenance hemodialysis (MHD). The 32-year-old man presented in August 2016 with a complaint of left shoulder swelling of 8 months' duration with no trauma or fever. He was diagnosed with nephrotic syndrome in 1998, which progressed to ESRD. He commenced MHD in 2012. Examination at our hospital revealed a soft nontender swelling of the left shoulder. Blood biochemistry showed elevated serum urate, phosphate, ß2 microglobulin, and parathyroid hormone. Imaging revealed joint effusion and dense heterogenous deposition. Aspirate analysis showed urate crystals 3+, and culture yielded no growth. Following rheumatology review, the working diagnosis was periarticular tissue tuberculosis, after excluding pseudogout and amyloidosis. Following 1 month of colchicine and allopurinol, synovial fluid microscopy showed CPDD crystals. Symptoms gradually resolved over the course of 6 months. In this rare case, a diagnosis of CPDD was made with a multidisciplinary approach that included imaging and biochemical investigations.

Current advances in therapies for calcium pyrophosphate crystal arthritis.

PURPOSE OF REVIEW: Calcium pyrophosphate (CPP) crystal disease is a common rheumatologic disorder that has received limited attention from the scientific community. This review is aimed at summarizing current evidence for managing CPP disease (CPPD), focusing on recently reported advances. RECENT FINDINGS: New data from case series indicate that interleukin-1ß inhibitors can help patients with refractory forms of CPPD. Methotrexate, formerly a promising agent, failed to demonstrate benefits in a recent trial, but still merits consideration for some patients. No significant advances on crystal dissolution have been achieved to date. Proper characterization of the CPP crystal disease picture is needed, ruling out the possible coexistence of another persistent arthritis unrelated to the CPP deposition. SUMMARY: Advances on CPP crystal dissolution and establishing definitions of the clinical spectrum of CPPD remain the main challenges for CPP crystal disease management.

Generalized annular granuloma associated with crowned dens syndrome, which resolved with colchicine treatment.

Granuloma annulare (GA) is a chronic, benign, and usually self-limiting cutaneous inflammatory disease, typically characterized by small, localized, skin-coloured papules that are usually asymptomatic or mildly pruriginous. Its aetiopathogenesis is still unknown and treatments are rarely effective. Generally, 50-70% of localized GA cases are self-limiting and show spontaneous resolution after 1-2 years, whereas disseminated GA is less likely to disappear without treatment. Treatment of generalized GA is usually based on single case reports, and only a few studies involving large case series have been published. We present the case of a patient affected by generalized GA, which resolved after colchicine treatment used for concomitant crowned dens syndrome due to calcium pyrophosphate deposition disease (CPPD). Colchicine may have worked by a direct action on GA or, alternatively, by controlling CPPD, as a possible trigger. As the low-dosage colchicine treatment was well tolerated by our patient, this could be easily used in the management of GA. However, further studies are needed to confirm the action of colchicine on GA.

Use of ultrasound for diagnosis and monitoring of outcomes in crystal arthropathies.

PURPOSE OF REVIEW: In the latest recommendations for the diagnosis and management of gout and calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, the diagnostic potential of ultrasound has been recognized. This review highlights the recent advances of research on ultrasound in gout and CPPD crystal deposition disease. RECENT FINDINGS: Ultrasound allows highly sensitive, noninvasive and quick detection of microcrystal aggregates in multiple anatomic areas. Ultrasound can be used as a safe and reliable guide to aspirate even minimal fluid collections suitable for microscopic analysis, and as a tool for monitoring monosodium urate crystal dissolution induced by urate-lowering therapy. The first metatarsophalangeal joint and the knee should be regarded as the anatomic regions with the highest probability of being respectively positive for monosodium urate and CPPD crystal aggregates. SUMMARY: The detection of highly evocative signs in patients with equivocal clinical findings may have a deep impact on the clinical decision-making process, narrowing the differential diagnostic spectrum and avoiding time-consuming and expensive diagnostic procedures. Ultrasound differential diagnosis between gout and CPPD crystal deposition disease is based on the characteristics of crystal aggregates and their preferential localization in different anatomical areas.

Crowned Dens Syndrome: Report of Three Cases and a Review of the Literature.

BACKGROUND: Patients with crowned dens syndrome (CDS), which is pseudogout of the atlantoaxial junction induced by "crown-like" calcifications around the dens, present with symptoms of severe neck pain, rigidity, and high fever. CDS patients are often misdiagnosed as having meningitis or polymyalgia rheumatica, leading to potentially unnecessary invasive procedures for diagnosis and treatment. CASE REPORT: We report 3 patients with CDS who had characteristic findings on computed tomography (CT), all of whom quickly recovered with nonsteroidal antiinflammatory drug (NSAID) administration. In addition, we reviewed 72 published cases, including our patients. CDS typically occurs in elderly people (mean age 71.4 years). Common symptoms include neck pain (100%), neck rigidity (98%), and fever (80.4%), and most show elevated inflammatory markers (88.3%) on serum laboratory tests. Neck pain on rotation is a characteristic and helpful symptom in the diagnosis. The most useful modality is CT (97.1%), showing linear calcium deposits around the dens, mostly in the transverse ligament of atlas (TLA). CT number is especially helpful to distinguish a normal TLA (35-110 HU) from a calcified one (202-258 HU) in our cases. The most effective treatment is NSAID administration (85%), which usually leads to marked resolution of symptoms within days or weeks. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Due to acute and severe symptoms, CDS patients often present to an emergency department. To avoid unnecessary invasive procedures for diagnosis and treatment, CDS should be considered in the differential diagnosis of febrile neck pain.

Safety and efficacy of colchicine in crystal-induced arthritis flare in 54 patients with severe chronic kidney disease.

INTRODUCTION: Colchicine, commonly used in gout flare, is contraindicated in severe chronic kidney disease (CKD) (estimated glomerular filtration rate <30 mL/min). However, in this context, there are few alternatives, and colchicine use persists. We evaluated the tolerance of colchicine and its efficacy in patients with severe CKD. PATIENTS AND METHODS: All prescriptions of colchicine for managing crystal-induced arthritis flare (gout or calcium pyrophosphate deposition (CPPD) disease) in a hospitalised patient with severe CKD were screened from September 2020 to September 2021. After patient consent and treatment information, clinical and biological safety and efficacy data were prospectively collected from day 1 (D1) to D11. RESULTS: We included 54 patients (median age 75 years (IQR 67-83)) with 62 colchicine prescriptions (cases). Twelve (22%) patients were on dialysis. The main reason for hospitalisation was heart failure (31.5%), acute renal failure (22.2%), infection (18.5%) or an acute joint episode (9.3%). In total, 59.3% of patients had diabetes. The prescriptions concerned 58 cases of gout flares, 1 case of CPPD and 3 cases of both. Initial colchicine dosages were ≤0.5 mg/day in 47/62 (75.8%) cases; no dosage exceeded 1 mg/day (median duration of 6 days (IQR 3-11)). Colchicine was well tolerated in 47/61 (77%) cases. No serious adverse event was reported. Colchicine was considered completely effective by the medical team in 48/58 (83%) of cases. CONCLUSION: The use of colchicine, at reduced doses, was mostly effective to treat crystal-induced arthritis flare in 54 patients with severe CKD and was well tolerated, without any serious adverse events.

Pseudogout in the early postoperative period after total knee arthroplasty.

Postoperative pseudogout after total knee arthroplasty is rare. If pseudogout attacks are misdiagnosed as periprosthetic sepsis, patients may undergo unnecessary surgical procedures. We report a case of pseudogout in the early postoperative period. The attack ensued shortly after a nonsteroidal antiinflammatory drug was discontinued. The diagnosis was confirmed by aspiration, and the patient improved after readministration of the nonsteroidal antiinflammatory drug. Although rare, pseudogout should be considered in the differential when approaching a suspected infection after total knee arthroplasty.

A single-centre retrospective case series of Anakinra for incident calcium pyrophosphate deposition disease.

In this 2-year retrospective case series, we characterise the calcium pyrophosphate deposition disease (CPPD) inpatient cohort at a single centre and assess the efficacy and safety of anakinra in its treatment. Adult inpatients with CPPD between 1st September 2020 and 30th September 2022 were identified by ICD-10 codes and confirmed based on clinical diagnosis and either CPP crystals on aspirate or chondrocalcinosis on imaging. Charts were reviewed for demographic, clinical, biochemical data, treatment choice, and response. Response to treatment was determined from chart documentation and calculated from time of first CPPD treatment. Daily responses to anakinra were recorded if anakinra was used. Seventy patients accounting for 79 cases of CPPD were identified. Twelve cases received anakinra, whilst 67 cases received conventional therapy only. Patient receiving anakinra were predominantly male, had multiple comorbidities, and had higher CRPs and serum creatinine when compared to the non-anakinra group. Anakinra was rapidly effective with the mean time to substantial and complete response being 1.7 and 3.6 days respectively. Anakinra was well tolerated. This study adds to the small amount of retrospective data present about the use of anakinra in CPPD. We observed a rapid response to anakinra in our cohort with minimal adverse drug reactions. Key Points • Treatment of CPPD with anakinra appears to be rapidly efficacious without safety concerns.

Confirming Prior and Identifying Novel Correlates of Acute Calcium Pyrophosphate Crystal Arthritis.

OBJECTIVE: To investigate previously identified and novel correlates of acute calcium pyrophosphate (CPP) crystal arthritis among well-characterized cases. METHODS: In this case-control study, we identified cases of acute CPP crystal arthritis using a validated algorithm (positive predictive value 81%) applied in the Partners HealthCare electronic health record (EHR). Cases were matched to general patient controls on the year of first EHR encounter and index date. Prespecified potential correlates included sex, race, and comorbidities and medications previously associated with CPP deposition/acute CPP crystal arthritis in the literature. We estimated odds ratios (ORs) and 95% confidence intervals using conditional logistic regression models adjusted for demographic characteristics, comorbidities, medications prescribed in the past 90 days, health care utilization, and multimorbidity score. RESULTS: We identified 1,697 cases matched to 6,503 controls. Mean ± SD age was 73.7 ± 11.8 years, 56.7% were female, 80.8% were White, and 10.3% were Black. All prespecified covariates were more common in cases than controls. Osteoarthritis (OR 3.08), male sex (OR 1.35), rheumatoid arthritis (OR 2.09), gout (OR 2.83), proton pump inhibitors (OR 1.94), loop diuretics (OR 1.60), and thiazides (OR 1.46) were significantly associated with acute CPP crystal arthritis after full adjustment. Black race was associated with lower odds for acute CPP crystal arthritis compared to White race (OR 0.47). CONCLUSION: Using a validated algorithm to identify nearly 1,700 patients with acute CPP crystal arthritis, we confirmed important correlates of this acute manifestation of CPP deposition. This is the first study to report higher odds for acute CPP crystal arthritis among males.

Case report: crowned dens syndrome in a patient with seronegative rheumatoid arthritis.

Chondrocalcinosis (CC) is the one of the most common crystal pyrophosphate disease associated arthritis in the elderly. It has been shown to coexist with seronegative and seropositive rheumatoid arthritis (RA), yet mostly with seronegative RA. Among the localisation of CC, the deposition in the ligaments surrounding the odontoid process may remain asymptomatic for years or may lead to and acute severe symptomatology, which may mimic several clinical illnesses among which meningitis (fever, severe pain, acute phase reactants). This is called the 'crowned dens syndrome (CDS)', which has been reported to represent an important percentage of acute neck pain needing hospital admission in neurosurgery units. In this case, the rapid demonstration of 'crowned dens' through CT scan may allow to avoid lumbar puncture and cerebrospinal fluid examination. The coexistence of RA and CDS is very rare, and rarely reported in the literature, yet it may represent a clinical challenge. We describe here one case that while on therapy with methotrexate (MTX) and naproxen (NPX) had an acute neck pain, and peripheral arthritis flare, that responded well to colchicine given along with MTX and NPX.