Acute Effects of Glucocorticoid Treatment, TNFα or IL-6R Blockade on Bone Turnover Markers and Wnt Inhibitors in Early Rheumatoid Arthritis: A Pilot Study.

Tumor Necrosis Factor (TNF)-α and Interleukin (IL)-6 play a fundamental role in bone loss in rheumatoid arthritis (RA), partly due to the inhibition of the Wnt canonical pathway. The aim of our study was to investigate the short-term effects of three different treatments on Wnt inhibitors (Dkk-1 and sclerostin) and on bone turnover markers (BTMs): N-propeptide of type I collagen (PINP) and C-terminal telopeptide of type I collagen (ß-CTX-I). We performed a retrospective analysis of prospectively collected data. We enrolled women affected by early RA (< 12 months) with active disease (DAS28 ≥ 2.6) despite a 6-month treatment with methotrexate (10-15 mg/week), who then started certolizumab pegol, tocilizumab, or methyl-prednisolone (8 mg/daily). Patients were divided into three groups according to the treatment. Blood samples were collected at baseline, week 1, and week 4. We selected 14 patients treated with certolizumab pegol, 14 patients with tocilizumab, and 20 patients with methyl-prednisolone. No difference between any of the tested parameters was found at baseline. ß-CTX-I, Dkk-1, and sclerostin decreased after 1 week of treatment with certolizumab pegol (- 27% ± 21.5, - 50% ± 13.2, and - 30% ± 30.4, respectively, p < 0.05). Methyl-prednisolone induced similar changes, albeit less marked, on ß-CTX-I and Wnt inhibitors, with a decrease in PINP (- 16.1% ± 16.5, p < 0.05). Tocilizumab did not significantly affect BTMs or Wnt inhibitors. No significant changes were found for PTH and 25OHD. In the first four weeks of treatment, TNFα inhibition showed strong effects on BTMs and Wnt inhibitors, differently from IL-6 blockade. Glucocorticoids induced similar changes; nonetheless, they showed undesired effects on bone formation.

Adenosine triphosphate: a new player in complex regional pain syndrome type 1.

The complex regional pain syndrome type 1 (CRPS-1) is one of the most discussed painful syndromes due to the variability and severity of its symptoms. CRPS-1 generally occurs after a trauma, a fracture or a sprain followed by an immobilization. Classical diagnostic criteria are not always clear; hence, the diagnosis is difficult. The definition of CRPS itself defines and considers the pain as key symptom neglecting the bone damage. Early CRPS involves the activation of the innate cutaneous immune system with altered sensory and sympathetic signaling, activation and proliferation of keratinocytes and mast cells in addition to the release of inflammatory mediators and pain. The role of the immune system and the response to the disease is becoming clearer as the microglia is activated as a result of injury and can induce a central sensitization while astrocytes can maintain the process. Adenosine triphosphate (ATP) exerts a fundamental role in the activation of innate cutaneous immune system, in the proliferation of keratinocytes and mast cells, in the release of several proinflammatory cytokines and in the microglia activation. It is essential to intervene on this pathology as soon as possible with drugs, as clodronate, able to reduce bone marrow edema and pain through the inhibition of the primary inflammatory process and the immune reaction, limiting the activation of macrophages and the release of cytokines activating nuclear growth factor (NGF). In this review the role of ATP, bisphosphonates and rehabilitation are discussed.

Clarithromycin in rheumatoid arthritis: the addition to methotrexate and low-dose methylprednisolone induces a significant additive value--a 24-month single-blind pilot study.

UNLABELLED: To compare the efficacy of the addition of clarithromycin (CM) to methotrexate (MTX) and methylprednisolone (MP) in active rheumatoid arthritis (RA). 32 patients with RA consecutively randomized. CONTROL GROUP: sixteen patients treated for 24 months with MTX 10-15 mg i.m. weekly and MP 4-6 mg daily. CM group: sixteen patients treated with MTX 10-15 mg i.m. weekly and MP 4-6 mg daily for 24 months; CM therapy added in the first month (500 mg twice a day for the first 15 days followed by 500 mg a day for the remaining 15 days). Evaluation of the improvement following ACR criteria was performed at months 1 (primary endpoint), 3 and 6. Patients were furthermore observed after 12, 18 and 24 months from the study beginning. At month 1, following ACR70 improvement criteria, we found a significant additive value in CM group (10/16 = 63% vs 4/16 = 25%, p = 0.033--chi-square test). After discontinuation of CM, the difference between groups was anymore evident (month 3: CM group 10/16 = 63% vs control group 9/16 = 56%). At month 24, 7/16 (44%) in control group and 12/16 (75%) in CM group completed the follow-up. The addition of CM to MTX and MP can induce the remission ACR 70 in the majority of RA patients within 4 weeks, while MTX and MP alone need about 3 months to achieve the same result.

Mesenchymal Cells are a Promising -But Still Unsatisfying- Anti- Inflammatory Therapeutic Strategy for Osteoarthritis: A Narrative Review.

Osteoarthritis (OA) is a chronic disease with both degenerative and inflammatory characteristics, affecting the osteochondral unit with the involvement of cartilage, subchondral bone and periarticular tissues. OA can produce chronic pain with neuropathic and inflammatory characteristics, leading to an increased disability. OA is secondary to many predisposing factors where the inflammatory process plays a key role. To manage OA, it would seem logical to block the factors influencing the inflammatory process at different levels, T lymphocytes, neutrophils, and the balance between phenotype-1 macrophages (M1, pro-inflammatory) and phenotype-2 macrophages (M2 anti-inflammatory), the managing cells. The efforts to repair and rebuild the lost cartilage and the attempts to implant autologous or heterologous material, with or without growth factors and the administration of drugs or the use of medical devices, have failed their objective. TNF-alpha and IL-1 inhibitors can only have a transient effect on pain; intra-articular oxidized Low-Density Lipoproteins are able to stimulate the activation of M2, while growth factors need to be better investigated. Also, intra-articular injections of mesenchymal stem cells (MSC) can inhibit the proliferation of T-lymphocytes, leading to cartilage repair and to osteophytes inhibition thanks to the release of exosomes, nanosized particles which are the active components. Gut microbiota has a potential role in the development of OA and could be able to influence the response to therapeutic agents.

Tumor necrosis factors blocking agents: analogies and differences.

Five anti-TNF agents, infliximab, adalimumab, etanercept, golimumab and certolizumab pegol are approved worldwide for the treatment of RA. Anti-TNF agents, bind to and neutralize soluble TNF-alpha, but exert different effects on transmembrane TNF-alpha-expressing cells (TNF-alpha-producing cells). Differences on affinity and avidity for soluble and transmembrane TNF-alpha were showed. Different activity on cells apoptosis, complement-dependent cytotoxicity (CDC) antibody dependent cell-mediated cytotoxicity (ACDC) were described. Some dramatic changes in gene expression were seen with all the anti-TNFs. Reviewing the biology of transmembrane TNF-alpha and its interaction with anti-TNF agents will contribute to understanding the bases of differential clinical efficacy of these promising treatment modalities.

Clodronate and hydroxychloroquine in erosive osteoarthritis: a 24-month open randomized pilot study.

We evaluated the efficacy of clodronate for treating active erosive osteoarthritis of the hand and to compare it with hydroxychloroquine. Group A consisted of 24 patients treated for 24 months with clodronate 300 mg i.v. for 7 days, followed by clodronate i.m. 100 mg for 14 days every 3 months. Group B comprised 14 patients treated with hydroxychloroquine 400 mg daily for 30 days, followed by 200 mg daily for the next 11 months. In group A, 21/24 patients completed the trial and obtained significant pain reduction (p < 0.001), Dreiser's score (p = 0.012), and number of tender joints (p = 0.011). Strength of right (p = 0.04) and left (p = 0.016) hands, physician's global assessment (p ≤ 0.001), and patient's global assessment (p = 0.021) improved. In group B, 8/14 patients completed 12 months of the study, which showed the inefficacy of hydroxychloroquine and its lack of acceptance by patients (worsening pain and patient's global assessment). Therefore, enrolment was stopped. Differences between groups showed a pain decreasing trend for group A and a slightly increasing one for group B (p = 0.018). Physician and patient global assessments showed a strong increase in group A compared with group B (p < 0.001). Clodronate is effective in erosive osteoarthritis; hydroxychloroquine seems to be ineffective.

Role of the Osteochondral Unit in the Pathogenesis of Osteoarthritis: Focus on the Potential Use of Clodronate.

Osteoarthritis (OA) is a chronic disease characterized by inflammation and progressive deterioration of the joint. The etiology of OA includes genetic, phlogistic, dismetabolic and mechanical factors. Historically, cartilage was considered the target of the disease and therapy was aimed at protecting and lubricating the articular cartilage. The osteochondral unit is composed of articular cartilage, calcified cartilage, and subchondral and trabecular bone, which work synergistically to support the functional loading of the joint. Numerous studies today show that OA involves the osteochondral unit, with the participation therefore of the bone in the starting and progression of the disease, which is associated with chondropathy. Cytokines involved in the process leading to cartilage damage are also mediators of subchondral bone edema. Therefore, OA therapy must be based on the use of painkillers and bisphosphonates for both the control of osteometabolic damage and its analgesic activity. Monitoring of the disease of the osteochondral unit must be extensive, since bone marrow edema can be considered as a marker of the evolution of OA. In the present review, we discuss some of the pathogenetic mechanisms associated with osteoarthritis, with a particular focus on the osteochondral unit and the use of clodronate.

Cost-effectiveness treatment with Rituximab in patients with rheumatoid arthritis in real life.

The cost-effectiveness of treatments that have the potential to change the "natural history" of a chronic progressive disease has to be evaluated over the long term. Cost-effectiveness estimates have been based on the concept that, with treatment, patients will not progress to the next level(s) of disease severity or will take a longer time to progress, thus avoiding or delaying the high costs and low utility associated with more severe disease. This analysis focused on the use of Rituximab in treating patients with moderate to severe RA for whom at least one anti-TNFα blocking agent had failed. The aim of our study was to evaluate the cost-effectiveness in 32 patients with rheumatoid arthritis in therapy with a single infusion of Rituximab 1,000 mg given on days 1 and 15 of each month for 1 year. After 6 months of treatment, we observed for all 32 patients a total quality-adjusted life year (QALY) gained of 11,840 with an average of 0.37 QALY for a single patient, a treatment cost of euro 5,610 and a QALY/cost ICER (incremental cost-effectiveness ratio) of euro 15,114. After 1 year of treatment, we observed data for 28 patients with a total QALY gained of 11,480 with an average of 0.41 QALY for a single patient, a treatment cost of euro 9,690 and a QALY/cost ICER (incremental cost-effectiveness ratio) of euro 23,696. The benefit of using Rituximab is cost-effectiveness with a QALY/gained under the acceptable threshold of euro 50,000 in our observational study. These are important data for discussion from the economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.

Can clodronate be effective in the treatment of disabling hydroxyapatite crystal-deposition disease? A report of two cases.

Hydroxyapatite crystals are often deposited in the vicinity of joints, where they can cause a clinical periarthritis. Clodronate is a first-generation bisphosphonate that has the ability to reduce ectopic calcifications. Two women were affected by disabling calcific periarthritis of the shoulders lasting for years and resistant to any traditional drug (including glucocorticoids), infiltration and surgical treatment. We treated both patients with low-dose methylprednisolone added to intramuscular clodronate at the daily dose of 100 mg administered for 20 days every 3 months for 5 cycles (18 months). In both cases, the results were clinically evident within 1 month, showing a significant reduction in pain and disability. After 18 months, the result was furthermore radiologically evident in both cases with a great reduction in the size of calcifications. These improvements were still present at follow-up after 7 and 5 years with complete functional recovery.

Long-term methotrexate use in rheumatoid arthritis patients: real-world data from the MARTE study.

BACKGROUND: The MARTE study investigated the demographic, clinical, and therapeutic characteristics of rheumatoid arthritis (RA) patients ongoing methotrexate (MTX) treatment for longer than 8 years. METHODS: This cross-sectional, observational study considered 587 RA patients from 67 Rheumatology Units across Italy. Data collected included demographic, clinical, and therapeutic characteristics, focusing on MTX prescription patterns (route of administration, dosing regimens, treatment duration, and discontinuation). RESULTS: As initial therapy, 90.6% of patients received one conventional synthetic Disease Modifying Anti Rheumatic Drug (csDMARD), with treatment started within the first 3 months from diagnosis in half of the patients. MTX was the first csDMARD in 46.2% of patients. The prevalent route of administration at diagnosis was the intramuscular (60.5%), while at study entry (baseline) 57.6% were receiving subcutaneous MTX. Patients who required a higher MTX dose at study entry were those who received a significantly lower starting MTX dose (P<0.001). Significantly higher MTX doses were currently required in men (P<0.001), current smokers (P=0.013), and overweight patients (P=0.028), whereas patients on oral therapy received significantly lower doses of MTX (P<0.001). CONCLUSIONS: The MARTE study confirms once again the potential of the proper use of MTX in the treatment of RA. Data from our study suggest that a higher dose of MTX should be used since the first stages in overweight patients, men, and smokers.

Clarithromycin in adult-onset Still's disease: a study of 6 cases.

Adult-onset Still's disease (AOSD) is a rare rheumatological condition characterized by an acute systemic involvement. There are no treatment guidelines. Glucocorticoids (GC), methotrexate (MTX), cyclosporin A and biologic agents have been successfully used, often in association. We treated six cases of AOSD with clarithromycin (CM) in combination with low-mild dose of GC and MTX. Four of them were not responsive to high-dose GC added to DMARDs, while two of them were treated with low-mild dose of GC added to CM from the beginning. CM, 500 mg b.i.d., was added to a mild-low dose of GC and to MTX. The dose of the drugs was reduced (and stopped where possible) following clinical and laboratory parameters. ACR criteria were used to assess clinical improvement. At 6 months 5 patients reached ACR 70% and could stop any therapy in 6-18 months; 1 continued chronic therapy with low-dose GC added to CM and MTX to maintain ACR 50%. CM can be a useful drug for the treatment of AOSD, even in patients not responsive to high-dose GC and DMARDs. No definitive conclusion can be drawn based on the present study.

What Do We Know About Clodronate Now? A Medical and Veterinary Perspective.

There has recently been some controversy over the use of bisphosphonates in horses and some confusion regarding the different classes of bisphosphonates and the differences between the mechanism of actions and effects of each class. This review article explores the different bisphosphonate classes and their different effects and mechanisms of action based on research from both the human and equine veterinary fields. This collaborative review between veterinary surgeons and medical doctors describes the latest use of bisphosphonates in humans and horses, including safety aspects, and allows comparisons to be drawn between the two fields. Potential future uses of bisphosphonates are also discussed.

Use of clodronate for painful knee prosthesis in osteoarthritis patients: a 6-month pilot study.

BACKGROUND: Knee replacement surgery is one of the most common surgical procedures performed worldwide. Unfortunately, knee prostheses can become painful over time, necessitating appropriate analgesic treatment. Bisphosphonates such as clodronate (CLO) may play an important role in the treatment of painful knee prostheses by virtue of its analgesic and anti-inflammatory properties. METHODS: In this prospective open label pilot study, eighteen consecutive patients aged 73.2±8.9 years affected by knee painful prosthesis and osteoarthritis were treated with a rehabilitation cycle in addition to i.v. or i.m. CLO. Induction dose was 2.0-2.1g, followed by a weekly dose of 200 mg (i.m.) for 6 months. Visual analogue scale (VAS) pain score and Tegner Lysholm Score (TLS) were used to assess improvement following CLO treatment. RESULTS: Thirteen out of 18 patients completed the 6-month follow-up. VAS pain score decreased from 8.1±1.8 at baseline to 5.6±2.6 (P<0.05) and TLS increased from 40.4±20.3 at baseline to 62.7±24.1 at 6 months (P<0.05). Univariate regression revealed that among a range of variables, BMI was positively correlated with VAS (r=0.73, P=0.004) and lower TLS after 1 month (r= -0.62, P=0.006). CONCLUSIONS: CLO in association with rehabilitation exercises can reduce pain and ameliorate the functionality of painful knee prostheses. Administration of a high dose (induction dose) of CLO every 3 months appears to be the most effective regimen compared to a weekly maintenance dose.

Physical Activity Prevents Cartilage Degradation: A Metabolomics Study Pinpoints the Involvement of Vitamin B6.

Osteoarthritis (OA) is predominantly characterized by the progressive degradation of articular cartilage, the connective tissue produced by chondrocytes, due to an imbalance between anabolic and catabolic processes. In addition, physical activity (PA) is recognized as an important tool for counteracting OA. To evaluate PA effects on the chondrocyte lineage, we analyzed the expression of SOX9, COL2A1, and COMP in circulating progenitor cells following a half marathon (HM) performance. Therefore, we studied in-depth the involvement of metabolites affecting chondrocyte lineage, and we compared the metabolomic profile associated with PA by analyzing runners' sera before and after HM performance. Interestingly, this study highlighted that metabolites involved in vitamin B6 salvage, such as pyridoxal 5'-phosphate and pyridoxamine 5'-phosphate, were highly modulated. To evaluate the effects of vitamin B6 in cartilage cells, we treated differentiated mesenchymal stem cells and the SW1353 chondrosarcoma cell line with vitamin B6 in the presence of IL1ß, the inflammatory cytokine involved in OA. Our study describes, for the first time, the modulation of the vitamin B6 salvage pathway following PA and suggests a protective role of PA in OA through modulation of this pathway.

Anti-nucleosome antibodies as prediction factor of development of autoantibodies during therapy with three different TNFalpha blocking agents in rheumatoid arthritis.

Anti-nucleosome antibodies have a role in the diagnosis and follow-up of systemic lupus erythematosus (SLE) and have a possible correlation with SLE activity and with kidney and hematological involvement. The aim of our study was to detect in 91 patients with rheumatoid arthritis (RA) the positivity of anti-nucleosome antibodies during therapy with three different TNFalpha blocking agents and to underline the possible correlation with the development of antinuclear autoantibodies (ANA) and anti-dsDNA autoantibodies. We detected anti-nucleosome antibodies, ANA, and anti-dsDNA during therapy with three different TNFalpha blocking agents at T-0 and after 12 and 24 weeks of treatment, respectively. Anti-nucleosome antibodies (IgG class) were analyzed by ELISA technique (Orgentec Diagnostika GmbH, Mainz, Germany), ANA both by indirect immunofluorescence (IIF) technique on Hep-2 (Scimedx, USA) and by ELISA (Autoimmune EIA ANA screening test Bio-Rad Laboratories, CA, USA), and anti-dsDNA (IgG and IgM classes) by ELISA (Kallestad, Bio-Rad Laboratories, CA, USA) and confirmed by IIF on Crithidia luciliae (ImmunoConcepts N.A., Sacramento, CA, USA). We observed 19 patients on infliximab treatment at 3 mg/kg every 8 weeks, 43 patients on etanercept treatment at 25 mg twice a week, and 29 patients on adalimumab treatment at 40 mg every other week. At baseline, we observed positivity as follow: in the group of patients treated with infliximab-anti-nucleosome 1/19 (5.26%), ANA 3/19 (15.7%), anti-dsDNA 1/19 (5.26%); in the group treated with etanercept--anti-nucleosome 2/43 (4.65%), ANA 1/43 (2.43%), anti-dsDNA 0/43; and in the group treated with adalimumab--anti-nucleosome 2/29 (6.89%), ANA 1/29 (3.44%), anti-dsDNA 0/29. The results at 12 weeks for the three autoantibodies were: for infliximab--3/19 (15.7%), 10/19 (52.6%), 2/19 (10.5%); for etanercept--3/43 (6.9%), 10/43 (23.2%), 1/43 (2.32%); and for adalimumab--3/29 (10.3%), 4/29 (13.7%), 1/29 (3.4%). At 24 weeks, the results were for infliximab 6/19 (31.5%), 12/19 (63.1%), 2/19 (10.5%); for etanercept 11/43 (25.5%), 22/43 (51.1%), 2/43 (4.65%); and for adalimumab 4/29 (13.7%), 13/29 (44.8%), 1/29 (3.4%). We observed a concordance anti-nucleosome/ANA antibodies of 85.5% (p < 0.001). Our data showed a concordance between anti-nucleosome antibodies and ANA positivity in patients with RA during therapy with TNFalpha blocking agents. The induction of autoantibodies positivity is different for each TNFalpha blocking agent.

Complete clinical and functional recovery following low-dose methotrexate related paraparesis in a patient with compound c.1298A>C AND c.677C>T MTHFR polymorphism: A case report.

RATIONALE: The mechanisms of action of MTX (methotrexate) in the treatment of RA (rheumatoid arthritis) and PsA (psoriatic arthritis) is related to its antifolic activity, due to the high affinity for enzymes that require folate cofactors as dihydrofolate reductase and to the anti-inflammatory activity derivated from the inhibition of thymidylate synthetase that leads to the over-production of adenosine. PATIENT CONCERNS: Our patient was a 41-year-old female, affected by PsA in treatment since 2 years with low-dose methylprednisolone and low-dose subcutaneous MTX. The treatment was effective. The patient subacutely developed a severe paraparesis with impossibility of gait or standing without aid and was admitted to a Neurology Department where the cause of the paraparesis was not clear in spite of accurate radiological neurophysiologic and laboratory tests. Therefore, she was admitted in a rehabilitation unit. DIAGNOSIS AND INTERVENTIONS: Paraparesis in PsA patient in treatment with methotrexate. MTX toxicity was hypothesized; therefore the drug was discontinued while i.m. folic acid and cyanocobalamin were administered for 20 days. The diagnosis was clinical, based on neurological examination (paraparesis) and on the chronic use of MTX (hypothesis of toxicity). OUTCOMES: The patient obtained a complete resolution of paraparesis. Genetic analyses showed associated a compound heterozygosity for the c.1298A>C and c.677C>T variants of methylenetetrahydrofolate reductase (MTHFR) gene. LESSONS: Neurological side effects of MTX are uncommon. In literature no previous case of MTX induced paraparesis in patients treated with low-dose MTX for chronic arthritis has been described. The association between the gene polymorphisms of MTHFR (c.1298A>C and c.677C>T) and MTX toxicity in arthritis patients is confirmed. The case also confirms that folates are a precious antidote of MTX toxicity.

Clodronate in the management of different musculoskeletal conditions.

INTRODUCTION: Clodronic acid is a non-nitrogen-containing bisphosphonate largely used from some decades in the prevention and treatment of postmenopausal and secondary osteoporosis. In addition to antiresorptive activity, clodronate has shown anti-inflammatory and analgesic properties, and modulatory effects on bone and cartilage metabolism. EVIDENCE ACQUISITION: A literature review has been conducted to characterize the mechanism of action of clodronate and to retrieve available evidence about the use of clodronate in primary and secondary osteoporosis, and its potential role in other musculoskeletal conditions and orthopedic surgery. EVIDENCE SYNTHESIS: The efficacy and safety of the available clodronate formulations (oral, intravenous and intramuscular) in the prevention and treatment of postmenopausal and secondary osteoporosis, including corticosteroid-induced osteoporosis and bone mass loss secondary to endocrine, gastrointestinal and neoplastic diseases, have been demonstrated in a variety of clinical trials. The analgesic, anti-inflammatory, bone- and chondro-modulating properties of clodronate have allowed to expand its use in other musculoskeletal conditions to those currently approved. Clodronate has proven to be beneficial in the treatment of osteoarthritis of the knee and of the hand, in the management of complex regional pain syndrome, and in the peri- and postoperative phase in subjects undergoing arthroplasty. CONCLUSIONS: The analysis of the available literature has shown that clodronate has relevant musculoskeletal effects beyond the antiresorptive activity. Further research is needed to better position clodronate therapy in the management of these conditions and to define the optimal formulation and dose regimen in any of the tested new indications.

Correction to: Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial-The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation).

One of the author names on this article was incorrectly tagged during the article mark-up; Luca Dalle Carbonare's name has now been correctly tagged, with first name 'Luca' and last name 'Dalle Carbonare'.