Challenges in the diagnosis and treatment of disabling pansclerotic morphea of childhood: case-based review.

Disabling pansclerotic morphea of childhood (DPMC) is a rare subtype of juvenile localized scleroderma (JLS) characterized by pansclerosis mainly affecting children under the age of 14. This aggressive disease has a poor prognosis due to the rapid progression of deep musculoskeletal atrophy resulting in cutaneous ulceration and severe joint contractures. We describe the challenges in treating a previously well 5-year-old male who has refractory symptoms of DPMC. Over the 29 months, since his initial presentation, we trialed over ten therapies. There was subjective improvement with prednisolone and mycophenolate mofetil (MMF). However, other therapies including biologics and tyrosine kinase inhibitors (TKI) were ineffective. The patient has been referred for hematopoietic stem cell transplant given ongoing disease progression. We conducted a literature search focusing on English articles with keywords including DPMC. Publications with limited information or describing cases aged 20 and above were excluded. Thirty-seven case reports were identified and the reported treatments were evaluated. Methotrexate and corticosteroids have been the most commonly utilized. MMF has been anecdotally effective. Biologics, TKI, and Janus kinase inhibitors lack evidence in DPMC, but have had demonstrated efficacy in similar pathologies including systemic sclerosis, and, thus, have been used for DPMC. Phototherapy has been documented to be reducing skin thickness and stiffness of plaques. Eventually, most children require multi-modal and high-dose immunosuppressive therapies to reduce the inflammation inflicted by the disease. Long-term antibiotics and nutritional support are important in the ongoing care of these patients.

Evidence of the symptomatic and structural efficacy of methotrexate in daily practice as the first disease-modifying drug in rheumatoid arthritis despite its suboptimal use: results from the ESPOIR early synovitis cohort.

OBJECTIVE: To describe the use of MTX in early arthritis (EA) in daily clinical practice and to evaluate its 6-month symptomatic efficacy and 12-month structural efficacy. METHODS: Patients included in the French observational ESPOIR cohort were assessed. Evaluation of the symptomatic and structural efficacy was performed by generalized linear regression after adjustment on propensity score (PS) in the group of patients receiving at least 3 months of MTX vs the ones receiving any other treatment except LEF, SSZ or TNF inhibitors. RESULTS: Within the first 6 months of follow-up of 777 EA patients, 59% received a DMARD, which was MTX in 68% (N = 313) of patients. The mean dose of MTX was 12.7 ± 3.8 mg/week. Only 53.7% of the patients received folic acid supplementation. MTX was initiated in patients with more active and severe disease. At 6 months, in unadjusted analysis, patients starting MTX had a significantly higher DAS-28 (3.58 vs 3.23; P = 0.001) and a significantly higher HAQ (0.60 vs. 0.48; P = 0.01) compared with controls. After adjustment by PS, there were no significant differences. Adjustment for the PS also revealed a statistically significant decrease in the radiological progression at 12 months in the MTX group [total Sharp-van der Heijde score (SHS), 1.05 ± 0.29 vs 2.02 ± 0.29, P = 0.025]. CONCLUSION: This study confirms the symptomatic and structural efficacy of MTX in EA in daily practice despite the non-optimal use of MTX, including low doses and infrequent concomitant folic acid supplementation.

A peripheral neuroimmune link: glutamate agonists upregulate NMDA NR1 receptor mRNA and protein, vimentin, TNF-alpha, and RANTES in cultured human synoviocytes.

Human primary and clonal synovial cells were incubated with glutamate receptor agonists to assess their modulating influence on glutamate receptors N-methyl-d-aspartate (NMDA) NR1 and NR2 and inflammatory cytokines to determine potential for paracrine or autocrine (neurocrine) upregulation of glutamate receptors, as has been shown for bone and chondrocytes. Clonal SW982 synoviocytes constitutively express vimentin, smooth muscle actin (SMA), and NMDA NR1 and NR2. Coincubation (6 h) with glutamate agonists NMDA (5 microM), and the NMDA NR1 glycine site activator (+/-)1-aminocyclopentane-cis-1,3-dicarboxylic acid (5 muM), significantly increases cellular mRNA and protein levels of glutamate receptors, as well as increasing vimentin, SMA, tumor necrosis factor-alpha, and RANTES (regulated on activation, normal T-cell expressed and secreted), assessed qualitatively and quantitatively with nucleotide amplification, image analysis of immunocytochemical staining, fluorescein-activated cell sorting, Western blotting, and immunoassays. Human primary synovial cells harvested from patients with arthritic conditions also constitutively expressed NMDA NR1 with increases after agonist treatment. Glutamate receptor agonist-induced increases were blocked by the noncompetitive glutamate antagonist MK-801 (8 microg/ml) and NR1 blocking antibody. Coincubation with glutamate agonists and phorbol 12-myristate 13-acetate, a protein kinase C activator, significantly enhanced mean levels of TNF-alpha and RANTES in SW982 cell supernatants compared with incubation with either agent alone. Increases were diminished with protein kinase inhibitor and NR1 blocking antibody. The functional activation of glutamate receptors on human synoviocytes establishes a neurogenic cell signaling link between neurotransmitter glutamate released from nerve terminals and target cells in the joint capsule. The influence of glutamate on subsequent release of cellular proinflammatory mediators in non-neural tissue for activation of downstream immune events supports a peripheral neuroimmune link in arthritis.

Angiogenesis inhibition as a therapeutic approach for inflammatory synovitis.

Angiogenesis inhibition, long studied in the treatment of malignancies, has begun to emerge as a potential therapeutic approach in managing inflammatory arthritis, particularly rheumatoid arthritis. The growth of new vessels is required for the development of the rheumatoid pannus, which then leads to extensive synovial inflammation and joint destruction. Vascular endothelial growth factor is the best studied mediator of angiogenesis, and several therapies have been developed that specifically target this molecule. Several other angiogenesis mediators, such as the angiopoietin-TIE system, hypoxia inducible factor and integrin alpha(V)beta(3), as well as naturally occurring inhibitors of angiogenesis, are also being investigated as potential therapeutic targets. Additionally, there are a number of drugs, including paclitaxel, 2-methoxyestradiol and fumagillin analogs, that might have a role in inhibiting angiogenesis and, thus, in treating proliferative synovitis.

Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: in vivo analyses in rodent models of arthritis and ex vivo analyses in human inflammatory synovitis.

OBJECTIVE: Angiotensin II (Ang II) is known to have proinflammatory actions, and Ang II type 1 (AT(1)) receptors are up-regulated in the rheumatoid synovium, suggesting that this receptor could be a therapeutic target. The purpose of this study was to investigate the antiinflammatory potential of the selective AT(1) receptor antagonist losartan, which is currently used for the treatment of cardiovascular disease. METHODS: Dose-ranging studies of losartan (1-50 mg/kg) were initially conducted in a rat model of acute (carrageenan/kaolin) arthritis, with subsequent evaluation in a rat model of adjuvant-induced arthritis (Freund's complete adjuvant). Losartan (10(-10) to 10(-6)M) was further tested ex vivo in human inflammatory synovitis, using collagenase-digested synovium. RESULTS: Western blot and immunohistochemical analyses both revealed a substantial increase in AT(1) receptor protein content in synovium from acutely and chronically inflamed rat knee joints. Similarly, synovial Ang I/II protein content was elevated during inflammation. Losartan inhibited acute joint inflammation in a dose-dependent manner, with 15 mg/kg being the optimal dose (and used in subsequent studies). Both prophylactic and therapeutic administration of 15 mg/kg of losartan substantially reduced knee joint swelling in rats with adjuvant monarthritis (> or =50%; P < 0.0001). Losartan also suppressed tumor necrosis factor alpha generation from inflamed human synovium in a dose-dependent manner (P < 0.05). CONCLUSION: Targeting the angiotensin pathway, particularly AT(1) receptors, could have significant therapeutic potential. Randomized placebo-controlled trials are now warranted to establish the extent to which angiotensin receptor blockers may provide antiinflammatory benefits.

Kinetic gait analysis assessment of meloxicam efficacy in a sodium urate-induced synovitis model in dogs.

OBJECTIVE: To examine the ability of meloxicam, a cyclooxygenase inhibitor, to mediate the effects of sodium urate-induced acute stifle synovitis in dogs. ANIMALS: 12 clinically normal adult hound-type dogs. PROCEDURE: A blinded, randomized, controlled single crossover design study was performed to determine the efficacy of meloxicam, using 2 dosage groups. In 2 experimental phases, dogs, according to group, received meloxicam (0.1 or 0.5 mg/kg of body weight) or matched volume of meloxicam vehicle, with a washout period of 21 to 28 days between phases. Blood samples for hematologic and biochemical analysis, as well as synovial fluid or cytologic analysis, were collected immediately before and approximately 24 hours after articular challenge of dogs under propofol anesthesia. Ground reaction forces (GRF) and subjective clinical scores were determined before and at 4, 8, 12, and 24 hours after articular challenge. Vertical force data included peak force, impulse, limb loading, and unloading rates. Craniocaudal data were divided into braking and propulsion phases and consisted of peak force and associated impulses. RESULTS: Except for propulsion impulse at 24 hours, all GRF variables were significantly greater at all post-synovitis induction times in the group receiving the high meloxicam dose. Significant differences in all GRF variables were seen at various times between the low-dose meloxicam group and the corresponding control group, and between the low- and high-dose meloxicam groups. Similar significance was seen in the subjective clinical evaluations. Strong correlations existed between the subjective and objective data. CONCLUSIONS: Meloxicam was effective in attenuating the effects of sodium urate-induced acute synovitis in dogs. Kinetic gait data provided an objective measurement of lameness in an experimentally induced arthritis model and quantified lameness improvements in response to medication with a nonsteroidal anti-inflammatory drug.

Acceleration of experimental lapine osteoarthritis by calcium pyrophosphate microcrystalline synovitis.

OBJECTIVE: To investigate the effects of chronic calcium pyrophosphate dihydrate (CPPD) synovitis on the development of osteoarthritic (OA) lesions in an animal model. METHODS: OA was induced in the right knees of 30 male New Zealand white rabbits by partial lateral meniscectomy and section of the fibular collateral and sesamoid ligaments (PLM/LS), followed by 8 weekly intraarticular (IA) injections of 1 mg (low-dose) or 10 mg (high-dose) of CPPD crystals in 3 sets of experiments (10 rabbits each). The contralateral left knees served as controls: experiment 1 PLM/LS alone, experiment 2 8 weekly IA injections of CPPD crystals alone, and experiment 3 sham surgery plus 8 weekly IA injections of CPPD crystals. RESULTS: At 8 weeks, repeated IA injections of low-dose and high-dose CPPD crystals into meniscectomized right knees resulted in more severe OA than in meniscectomized but noninjected left knees (experiment 1) (P = 0.003 and P = 0.001, respectively). One-fourth of the meniscectomized knees (11 of 40), both CPPD-injected and noninjected, showed embedded synovial cartilage shards. CONCLUSION: The data demonstrate a worsening effect of chronic CPPD crystal-induced synovitis on experimental OA produced in the rabbit knees by PLM/LS, and support a possible role for CPPD microcrystalline inflammation in the progression of OA lesions in clinical CPPD crystal deposition disease.

Synovitis reduced by inhibition of leukotriene B4. Carrageenan-induced gonarthritis studied in dogs.

The pathophysiologic significance of leukotriene B4 (LTB4) in arthritis was studied in dogs by unilateral intraarticular deposition of 15-hydroxy-eicosatetraenoic acid (15-HETE), an endogenous inhibitor of the formation and the effects of LTB4, in bilateral carrageenan-induced gonarthritis. LTB4 in synovial fluid was selectively inhibited in 15-HETE treated joints, the formation of prostaglandin E2 (PGE2) being largely unaffected. The clinical symptoms, intraarticular pressure, and extractable synovial fluid volume were reduced in treated joints. No effect could be discerned regarding blood flow in the synovial membrane, capsule, or juxta-articular bone as measured by tracer microspheres; and no effect on bone metabolism was found as judged by 99mTc-diphosphonate uptake. Thus, inhibition of LTB4 reduces joint exudation, but does not seem to interfere with changes in juxta-articular hemodynamics or bone metabolism following synovial inflammation.

Synovial plicae syndrome.

The suprapatellar, medial patellar, and infrapatellar plicae are three embryonic remnants of synovial tissues that are often a cause of intermittent anterior knee pain. A primary blunt trauma or internal pathological derangement will result in the plicae becoming thickened and inelastic with an often inappropriate diagnosis of meniscal tear. The signs, symptoms and examination findings when combined with special testing enables the doctor to correctly establish a diagnosis and proceed with treatment. The chiropractic doctor may play a prime role in the conservative method of treatment and prevent further dysfunction leading to surgical excision as the treatment of choice. This paper will review and summarize the current knowledge of plicae anatomy, pathophysiology, diagnosis and therapeutics in an attempt to provide chiropractors with an increasing awareness of the synovial plicae syndrome.

The antialgesic drugs: human therapeutic correlates of their potency in laboratory animal models of hyperalgesia.

This survey discusses the correlation between the oral potency of antialgesic drugs in several pharmacology laboratories and their human oral dose in clinical practice. We also present a brief overview of a few biological assays that have been successfully used to direct the synthesis of newer antialgesic drugs. The laboratory assay that our analysis showed to be most predictive of the clinical analgesic dose is based upon the response of rats to flexion of an arthritic joint. Laboratory ED50 values from the ACh-induced abdominal constriction assay in mice are nearly as predictive while the predictive power of the yeast-induced hyperalgesia assay in rats is somewhat less. Probably because of the small number of experiments, the correlation between the efficacy of these agents in a canine model of synovitis and their clinical doses only reached borderline statistical significance (p = 0.0651). Regression equations are presented that permit calculations of single clinical analgesic doses from efficacy data in individual tests. Calculation of stepwise multiple regression showed that the clinical dose could be best predicted when efficacy data obtained in the joint flexion assay in rats and the ACh-induced constriction assay in mice are both taken into account. We have concluded that the effective doses are highly predictive of clinical efficacy because these animal assays have been designed to reflect the action of drugs upon prostanoid-induced hyperalgesia.