Chronic Pyrophosphate Arthropathy Research Articles

New Proteins Contributing to Immune Cell Infiltration and Pannus Formation of Synovial Membrane from Arthritis Diseases.

An inflamed synovial membrane plays a major role in joint destruction and is characterized by immune cells infiltration and fibroblast proliferation. This proteomic study considers the inflammatory process at the molecular level by analyzing synovial biopsies presenting a histological inflammatory continuum throughout different arthritis joint diseases. Knee synovial biopsies were obtained from osteoarthritis (OA; n = 9), chronic pyrophosphate arthropathy (CPPA; n = 7) or rheumatoid arthritis (RA; n = 8) patients. The histological inflammatory score was determined using a semi-quantitative scale based on synovial hyperplasia, lymphocytes, plasmocytes, neutrophils and macrophages infiltration. Proteomic analysis was performed by liquid chromatography-mass spectrometry (LC-MS/MS). Differentially expressed proteins were confirmed by immunohistochemistry. Out of the 1871 proteins identified and quantified by LC-MS/MS, 10 proteins (LAP3, MANF, LCP1, CTSZ, PTPRC, DNAJB11, EML4, SCARA5, EIF3K, C1orf123) were differentially expressed in the synovial membrane of at least one of the three disease groups (RA, OA and CPPA). Significant increased expression of the seven first proteins was detected in RA and correlated to the histological inflammatory score. Proteomics is therefore a powerful tool that provides a molecular pattern to the classical histology usually applied for synovitis characterization. Except for LCP1, CTSZ and PTPRC, all proteins have never been described in human synovitis.

Proteins involved in the endoplasmic reticulum stress are modulated in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components. The aim of this work is to provide evidence that similar inflammatory mechanisms exist in synovial membrane (n = 24) obtained from three pathologies presenting altogether an inflammatory gradient: OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). Synovial biopsies were first characterized by a histological score based on synovial hyperplasia and infiltration of lymphocytes, plasma cells, polymorphonuclear and macrophages. All biopsies were also analyzed by 2D-nano-UPLC-ESI-Q-Orbitrap for protein identification and quantification. Protein levels were correlated with the histological score. Histological score was in the range of 3 to 8 for OA, 5 to 13 for CPPA and 12 to 17 for RA. Of the 4,336 proteins identified by mass spectrometry, 51 proteins were selected for their strong correlation (p < 0.001) with the histological score of which 11 proteins (DNAJB11, CALR, ERP29, GANAB, HSP90B1, HSPA1A, HSPA5, HYOU1, LMAN1, PDIA4, and TXNDC5) were involved in the endoplasmic reticulum (ER) stress. Protein levels of S100A8 and S100A9 were significantly higher in RA compared to OA (for both) or to CPPA (for S100A8 only) and also significantly correlated with the histological score. Eighteen complement component proteins were identified, but only C1QB and C1QBP were weakly correlated with the histological score. This study highlights the inflammatory gradient existing between OA, CPPA and RA synovitis either at the protein level or at the histological level. Inflamed synovitis was characterized by the overexpression of ER stress proteins.

Proteins involved in the endoplasmic reticulum stress are key players in synovitis of osteoarthritis, chronic pyrophosphate arthropathy and rheumatoid arthritis, and correlate with the histological inflammatory score

Purpose: It is now well recognized that osteoarthritis (OA) synovial membrane presents inflammatory components characterized by cellular proliferation, sub-intimal leukocytes infiltration and neovascularization. In this study, proteomics LC-MS/MS was applied to knee synovitis from patients with OA, chronic pyrophosphate arthropathy (CPPA) and rheumatoid arthritis (RA). The aim of this work was to provide evidence that similar inflammatory mechanisms in synovitis exist among the three pathologies presenting a histological inflammatory gradient.

Photobiomodulation of Pain and Inflammation in Microcrystalline Arthropathies: Experimental and Clinical Results

This article presents the results of laser therapy in crystal (hydroxyapatite, calcium pyrophosphate, and urates) deposition-induced arthritis in rats and the clinical applications in humans. Microcrystalline arthropathies are prevalent among geriatric patients, who are more vulnerable to the side effects of drugs. The effectiveness of laser therapy for pain relief, free of side effects, has been reported in painful conditions. Two milligrams of each of the above-mentioned crystals was injected in both joints of the back limbs in three groups of rats; these groups were then treated with laser irradiation. Three other groups received no treatment after the injections. We determined the plasmatic levels of inflammatory markers (fibrinogen, prostaglandin E2, and TNF(alpha)), tissues (prostaglandin E(2)) and conducted anatomopathological studies. Twenty-five patients with acute gout arthritis were randomized into two groups and treated over 5 days: group A, diclofenac 75 mg orally, twice a day; and group B, laser irradiation once a day. Forty-nine patients with knee chronic pyrophosphate arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Thirty patients with shoulder chronic hydroxyapatite arthropathy were randomized into two groups and treated over 21 days; group A, diclofenac 50 mg orally, twice a day; and group B, laser irradiation once a day. Fibrinogen, prostaglandin E(2), and TNF(alpha) concentrations in the rats injected with crystals and treated with laser decreased significantly as compared with the groups injected with crystals without treatment. Both laser therapy and diclofenac achieved rapid pain relief in patients with acute gouty arthritis without significant differences in efficacy. Laser therapy was more effective than diclofenac in patients with chronic pyrophosphate arthropathy and in patients with chronic apatite deposition disease. Laser therapy represents an effective treatment in the therapeutic arsenal of microcrystalline arthropathies.

Calcium pyrophosphate deposits--a chameleon

Calcium Pyrophosphate Dihydrate (CPPD) crystals deposit in articular fibro- or hyaline cartilage (chondrocalcinosis), joint capsules, synovium, periarticular ligaments and tendons resulting in an age dependent prevalence. These calcifications may be asymptomatic or may manifest as acute pseudogout arthritis, pseudorheumatoid arthritis, bursitis, tenosynovitis, tendinitis, polymyalgic syndrome or chronic pyrophosphate arthropathy. The diagnosis is based on the presence of intracellular CPPD crystals in synovial fluid detected by polarizing microscopy, the characteristic radiological changes and the typical clinical presentations. The therapy is symptom oriented or disease specific in case of an underlying metabolic disease such as hemochromatosis, hyperparathyroidism, hypophosphatasia, hypomagnesemia or hypothyroidism.

SYNOVIAL FLUID CALCIUM PYROPHOSPHATE DIHYDRATE CRYSTALS AND ALIZARAN RED POSITIVITY: ANALYSIS OF 3000 SAMPLES

Three thousand synovial fluids (1312 patients: chronic pyrophosphate arthropathy (CPA), 41%; osteoarthritis (OA), 12%; rheumatoid arthritis (RA), 16%) were examined for crystals, including calcium pyrophosphate dihydrate (CPPD), by polarized microscopy (score 0-3); calcific particles, by alizarin red positivity (ARP; 0-3); and total cell count. For 1150 fluids, local joint inflammation was assessed as 'active' or 'inactive' using a summated score of six clinical variables. CPPD and ARP scores did not correlate, but each showed positive correlation with age (P less than 0.01, P less than 0.02 respectively). Pseudogout had the highest mean CPPD score (P less than 0.001); intermittent CPPD positivity (range 8-100%) was seen in serially aspirated CPA joints, and there was no difference in CPPD positivity or score between active and inactive CPA. ARP was most frequent in OA subsets (72% of CPA, 46% of OA, 31% of RA; P less than 0.001). ARP was more frequent in active than inactive OA (P less than 0.05) but showed no association with inflammation in CPA or RA. Cell counts were higher in RA and pseudogout compared to OA and CPA, and in active compared to inactive RA. No correlation was found between ARP or CPPD scores and cell count. Cholesterol crystals were uncommon (0.2%) and showed no disease or joint predilection. In arthritic joints, CPPD and calcific particles particularly associate with the OA process and ageing. CPPD may contribute to acute and other calcific particles to chronic inflammation in OA.

Synovial fluid lactic acid in acute and chronic pyrophosphate arthropathy and in osteoarthritis.

A comparison of synovial fluid lactate levels has been made in cases of chronic pyrophosphate arthropathy (PA) with and without joint destruction, acute PA and osteoarthritis. No statistically significant difference could be observed between results of chronic PA and osteoarthritis. By contrast, synovial fluid lactate levels were significantly higher in acute PA in comparison with the two other groups. These data suggest that hypoxia is unlikely to play a role in destructive arthropathy commonly found in chronic PA.

Relation between synovial fluid C3 degradation products and local joint inflammation in rheumatoid arthritis, osteoarthritis, and crystal associated arthropathy.

C3 degradation products (C3dg/d) were estimated in 288 synovial fluid (SF) samples (rheumatoid arthritis (RA) 93, osteoarthritis (OA) 68, chronic pyrophosphate arthropathy 80, acute pseudogout 20, others 27) from knees of 138 patients (bilateral 67, serial sampling on two to six occasions 40). At each aspiration knees were defined as 'active' or 'inactive' by single observer global assessment using six clinical parameters of inflammation. Lack of correlation between paired SF and plasma C3dg/d implied local C3 activation within joints. Raised SF C3d levels were found in active compared with inactive RA joints (mean (range) 51 (15-105) and 6 (0-15) units/ml respectively). Low SF C3dg/d levels were found in OA (mean (range) 0.8 (0-7) units/ml) and chronic pyrophosphate arthropathy (mean (range) 4 (0-16) units/ml), irrespective of clinical activity. In contrast, very high levels (mean (range) 61 (16-126) units/ml) were present in all cases of pseudogout. These differences remained after correction for SF C3 or albumin. This study is the first to show a positive correlation between SF C3dg/d and local inflammation in RA joints. It further suggests that C3 activation is a constant feature of pseudogout but not an accompaniment of inflammation associated with chronic crystal associated synovitis or OA.

Double blind, placebo controlled trial of magnesium carbonate in chronic pyrophosphate arthropathy

Double blind, placebo controlled trial of magnesium carbonate in chronic pyrophosphate arthropathy

EFFECT OF INTRA-ARTICULAR YTTRIUM-90 ON CHRONIC PYROPHOSPHATE ARTHROPATHY OF THE KNEE

Fifteen patients with bilateral, symmetrical, chronic pyrophosphate arthropathy of the knee were given intra-articular injections of yttrium-90 (5 mCi) plus steroid (triamcinolone hexacetonide, 20 mg) into one knee, and saline plus steroid into the other (control) knee. Allocation of the 90Y injection was random and double blind. After 6 months there was significantly less pain, inactivity stiffness, joint-line tenderness, and effusion in the 90Y-injected knees than in the controls (p<0·01). There were also significant differences between 90Y-injected and control knees in the changes in range of movement (p<0·01) and joint circumference (p<0·05) caused partly by progression of disease in the control knees. No significant differences in joint deformity, instability, X-ray appearance, or synovial-fluid analysis were seen. In all cases patient and observer assessment favoured the treated side (p<0·01). These findings indicate that intra-articular 90Y may be of benefit in chronic pyrophosphate arthropathy, a disease for which there is no treatment. The predilection of this condition to affect the knees of the elderly makes such treatment highly suitable because the joint lends itself readily to injection and the procedure carries very few actual or potential risks in this age group.

Synovial Fluid Crystals

Synovial fluid was aspirated from the Joints of unselected groups of patients suffering from rheumatoid arthritis (30), osteoarthritis (34), pyrophosphate arthropathy (25) and gout (six). Specially selected patients with osteoarthritis (10) and other miscellaneous forms of arthropathy (six) were also Included. Total and differential cell counts were performed, and the fluids were examined by polarized light microscopy and analytical electron microscopy to determine crystal content. fluids from patients with rheumatoid arthritis and gout had a higher total cell count, and greater proportion of polymorphonuclear cells. There was no difference in the cell content in patients with osteoarthritis and chronic pyrophosphate arthropathy. Osteoarthritic fluids containing crystals did not have a significantly different cell count from those without. Polarized light microscopy was confirmed as a good technique for differentiating urate from pyrophosphate crystals. However, pyrophosphate crystals varied greatly in appearance, and were occasionally too small to be visualized. Crystals thought to be brushite, formed in some fluids after aspiration, causing confusion on polarized light examinations, and other unidentified birefringent material was often seen. Analytical and scanning electron microscopy revealed a wide variation in the morphology and elemental content of synovial fluid crystals. Hydroxyapatite crystals were identified in nine out of 34 unselected osteoarthrltlc fluids, in 10 selected cases, and six with synovitis of unknown cause. Hydroxyapatite was seen in combination with pyro phosphate in six cases, and was the only crystal identified in one case of ‘pyrophosphate’ nrthropathy. Small pyrophosphate crystals, not seen with the light microscope, were identified in two cases. Other crystalline particles containing calcium and phosphorus were seen in some cases, but could not be identified. No crystals were identified in rheumatoid arthritis fluids. Crystal phagocytosis was visualized using scanning electron microscopy. It is concluded that hydroxyapatite crystals are commonly present in synovial fluids in chronic arthritis, with or without pyrophosphate, and that a range of other calcium phosphate salts remain to be identified.