Intra-articular clodronate in patients with knee osteoarthritis non-responder to intra-articular hyaluronic acid - a case report series of 9 patients with 8-month follow-up.

Background: Osteoarthritis (OA) is a common disease in the elderly people, inducing pain and functional limitations. Clodronate (CLO) a first generation non-nitrogen containing bisphosphonate has been purposed as a treatment of OA, being effective on pain, inflammation, bone marrow oedema, osteophytosis and cartilage regeneration. Intra-muscular routes of CLO showed efficacy in the treatment of Knee OA (KOA) and erosive OA of the hand. In KOA intraarticular CLO at low doses (0.5-2 mg) showed efficacy as well as hyaluronic acid (HA), being able to improve the effectiveness if associated to HA. Methods: Nine Consecutive patients (4 female, 5 male, mean age 78,22) with KOA at 2nd or 3rd degree following Kellgren-Lawrance scale, non responder to HA and unintended to surgery. They were treated with intraarticular CLO at the weekly dose of 20 mg, plus lidocaine 1% in 5 cc of saline solution for a route of 5 weekly infil-trations, followed by a second route of 5 intraarticular infiltrations 3 months after the first course. Visual analog score (VAS) pain and Tegner-Lysholm Score (TLS) were used to assess changes following CLO treatment. Results: Baseline pain was 6,77/10, reduced to 1,09 at day 150 (after second course) and to 2,3/10 at day 240. TLS at baseline was 56,7/100, improved to 96,7 at day 150 and to 84,1 at day 240. At day 240 only 2 out of 9 patients had a negative judgement of the treatment and decided to stop it, while 7 were satisfied and available to a further course. There was no increase of consumption of anti-inflammatory or analgesic drugs. A short time lasting pain after the injections was registered in all patients. Conclusions: In a small cohort of patients affected by KOA, non responders to intraarticular HA a higher dose of intraarticular CLO in KOA showed good compliance, amelioration of pain and functionality.

Bone Marrow Edema: pathogenetic features.

Abstract: The term "bone marrow edema" was used for the first time in 1988 by Wilson. He noticed a high signal on fluid-sensitive sequences at MRI located in the subchondral bone. We can find bone marrow edema in many musculoskeletal diseases such as Inflammatory and Rheumatic diseases (Rheumatoid Arthritis, Spondylarthritis, etc.), Osteoarthritis (BMLs) and Bone Marrow Edema Syndromes (BMES). This classification is based on pathophysiological, histological and clinical differences despite the same imaging evidence. The distinction is useful also in terms of treatment. Bisphosphonates in association with NSAIDs or corticosteroids are the main therapy while TNF-a Inhibitors are used for the specific inflammatory origin. Bone marrow edema has become an important aspect to consider in the diagnostic path of the main musculoskeletal diseases. This paper starts from a systematic review of literature. We chose the most decisive contributions in order to develop a better description of the pathogenetic features about this "new" evidence.

Osteoarticular pain: therapeutic approach by paradigms.

Osteoarticular pain is a common condition in the adult population. It is a nociceptive pain modulated by different factors, and it is one of the major symptoms that force patients to seek medical advice. Since osteoarticular pain has a complex pathophysiology and it is not a linear condition, we propose in this paper an original approach to osteoarticular pain by paradigms, where a paradigm refers to a framework of concepts, results, and procedures within which subsequent work is structured. The paradigm presented is a conceptual tool that could help clinicians to choose the correct therapy considering both pain characteristics and clinical features.

Use of clodronate in the management of osteoarthritis: an update.

Osteoarthritis (OA) is a chronic rheumatic disease characterized by joint cartilage wear and loss of normal function. Clodronate (CLO) is a first-generation non-nitrogen-containing bisphosphonate that exerts anti-inflammatory and analgesic and modulatory effects on bone and cartilage metabolism. To date, few clinical studies have evaluated the effect of CLO in OA. Current evidence suggests that CLO may represent a new type of analgesic drug as it reduces pain in bone diseases characterized by edema such as Complex Regional Pain Syndrone type-1 and vertebral fractures. Thanks to its anti-inflammatory and analgesic effects, CLO has been shown to afford benefit in knee OA, erosive OA of the hand, painful knee hip prosthesis and veterinary practice. Transforming growth factor ß1 has also been found to play an important role in the pathogenesis of OA. The present review article examines recent evidence on the potential use of CLO in the treatment of OA.

Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study.

Osteoporosis and fractures are common and invalidating consequences of chronic glucorticoid (GC) treatment. Reliable information regarding the epidemiology of GC induced osteoporosis (GIOP) comes exclusively from the placebo group of randomized clinical trials while observational studies are generally lacking data on the real prevalence of vertebral fractures, GC dosage and primary diagnosis. The objective of this study was to evaluate the prevalence and incidence of osteoporotic fractures and to identify their major determinants (primary disease, GC dosage, bone mineral density, risk factors, specific treatment for GIOP) in a large cohort of consecutive patients aged >21 years, on chronic treatment with GC (≥5 mg prednisone - PN - equivalent) and attending rheumatology centers located all over Italy. Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) is a national multicenter cross-sectional and longitudinal observational study. 553 patients suffering from Rheumatoid Arthritis (RA), Polymyalgia Rheumatica (PMR) and Connective Tissue Diseases (CTDs) and in chronic treatment with GCs were enrolled. Osteoporotic BMD values (T score <-2.5) were observed in 28%, 38% and 35% of patients with CTDs, PMR or RA at the lumbar spine, and in 18%, 29% and 26% at the femoral neck, respectively. Before GC treatment, prevalent clinical fractures were reported by 12%, 37% and 17% of patients with CTDs, PMR, or RA, respectively. New clinical fragility fractures during GC treatment were reported by 12%, 10% and 23% of CTDs, PMR and RA patients, respectively. Vertebral fractures were the prevailing type of fragility fracture. More than 30% of patients had recurrence of fracture. An average of 80% of patients were in supplementation with calcium and/or vitamin D during treatment with GCs. Respectively, 64%, 80%, and 72% of the CTDs, PMR and RA patients were on pharmacological treatment for GIOP, almost exclusively with bisphosphonates. The GIOTTO study might provide relevant contributions to clinical practice, in particular by highlighting and quantifying in real life the prevalence of GIOP and relative fractures, the frequency of the main risk factors, and the currently sub-optimal prevention. Moreover, these results emphasize the importance of the underlying rheumatic disease on the risk of GIOP associated fractures.

Multifocal osteonecrosis in a patient with anamnestic ulcerative colitis. Is there a relationship with the disease and the use of glucocorticoids twenty years before? A brief review of the literature.

In 2013 a 40 year old man came to visit in our Rheumatology Unit because of a recent bilateral shoulder and hip pain. He had been treated from 1990 to 2000 with Cyclosporin A and Sulfasalazyn because of an ulcerative colitis which was completely in remission from 2000 . Glucocorticoids at the mean daily dose of 50 mg were administered only in the first period (1990-92). X-plain rays showed a suspicious multifocal osteonecrosis of both femoral and humeral heads. Magnetic Resonance confirmed the diagnosis (stage III and IV following Ficat and Arlet's criteria). The patient was treated with a cycle of hyperbaric oxygen therapy, with two cycles of intravenous clodronate and with a 2-month cycle of teriparatide. The treatment was able to save a sufficient function for both shoulders, while for both hips arthroplasty the surgery was required. The risks of osteonecrosis linked to inflammatory bowel diseases or to its therapy are discussed.

Atypical femoral fracture as first sign of non-hodgkin lymphoma- case report with a brief review of the literature.

ABSTRACT: Atypical subtrochanteric and diaphyseal femoral fractures (AFF) have been suggested to be associated with the use of bisphosphonates (BPs), but the role of these drugs is still under debate. A 64-year old female, never treated with BPs was admitted to our Rehabilitation Institute because of a recent right AFF. The patient began suffering from low back pain radiating to the groin and to the anterior regions of the right thigh and leg, A nuclear magnetic resonance (NMR) of the lumbar spine showed disc protrusions at the L3-L4 and L5-S1 levels with impingement of the spinal nerve root. Therefore she was treated with analgesic, anti-inflammatory and muscle relaxing compounds for nine months without reduction of symptoms. Being the pain still present, the patient felt down the street breaking the right femoral neck and the femoral distal shaft. Following the ASBMR criteria the fracture was classified as a complete AFF and the patient underwent surgical ostheosynthesis with nail. A bone biopsy of the fracture site was performed showing findings consistent with B-cells non-Hodgkin lymphoma (NHL). Immuno-histochemical analysis highlighted that the atypical cells were follicolar G2 pattern diffuse large B cells. CONCLUSIONS: AFF can occur also in patients not treated with BPs. In the present case report, the cause of the fracture was a NHL. Even uncommon, this occurrence should be considered in the differential diagnosis of radicular pain.

CLODRONATE: OLD DRUG, NEW USES.

Clodronate (CLO) is a bisphosphonate (BP) with proved efficacy in the treatment of osteoporosis. The reason of its activity is the anti-resorptive action, which is a common characteristic of BPs. Contrary to other BPs, CLO has a relatively low affinity for bone and a peculiar mechanism of action. CLO is effective in several diseases associated to excessive bone resorption as bone Paget’s disease and CRPS type I. Moreover, there are data showing activity of CLO in the erosive osteoarthritis of the hands, in the osteoarthritis of the knees, in the treatment of extra-articular calcifications and in preventing the mobilization of knee and hip prosthesis.

Determinants of Risk Infection During Therapy with Anti TNF-Alpha Blocking Agents in Rheumatoid Arthritis.

The use of TNF-alpha antagonists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety including infections have been observed. The aim of the study was to evaluate the changes in cytokines levels and cells subsets in patients with RA during anti TNF blocking agents treatment and the possible effect on infections' development. We evaluated in 89 RA patients [39 treated with etanercept (ETN), 29 with adalimumab (ADA) and 21 with infliximab (IFN)] at baseline and after 6 months the following parameters: procalcitonin, ESR, CRP, cytokines as TNF, IL-6, IL-10, IL-8 and the TNF/IL-10 ratio, and peripheral mononuclear cells as CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD3- /CD16+/56+, CD14+HLADR+, CD20+, CD19+/CD38+. Peripheral mononuclear cells were detected by flow cytometric system Cytomics FC500 and cytokines circulating levels by a quantitative sandwich enzyme immunoassay technique (Human IL-8 Instant ELISAe Bioscience, Human IL-6 Instant ELISA e Bioscience, Human IL-10 Instant ELISAe Bioscience and Human TNF-a Quantikine immunoassay RD system). A lower reduction of CD14+HLADR+ in ADA group 54.6±10.4% vs ETA 48.4±15.7% vs INF 40.7±16.5%, p<0.039 was found. No differences in all three groups on peripheral mononuclear cells CD3+, CD3+/CD4+, CD3+/CD8+, CD19+, CD 20+, CD19+/CD38+, CD3-/CD16+/56+, and cytokine circulating levels were found. The number of infections at 6 months was: 10.3% in ADA group, 12.8% in ETN group and 19.04% in IFN group. A correlation was found between the reduction in CD14+HLADR+ cells and IFN treatment. Our data showed that the level of CD14+HLADR+ cells was reduced during therapy with IFN. ADA and ETN don't reduce lymphocyte populations and their subsets such as CD14+HLADR+ cells that play an important role host defence.

Efficacy and safety of leflunomide or methotrexate plus subcutaneous tumour necrosis factor-alpha blocking agents in rheumatoid arthritis.

Several smaller retrospective case series have concluded that leflunomide (LEF) in combination with anti-TNF-alpha blocking agents appears to be effective and safe. Prospective case series and cohort studies have generally confirmed the efficacy of this combination. Overall, there is currently no evidence from controlled trials that an anti-TNF-alpha combination with LEF is as effective as an anti-TNF-alpha combination with methotrexate (MTX). We compared the effectiveness and safety of a therapeutic regimen associating subcutaneous anti-TNF-alpha agents, etanercept (ETN) and adalimumab (ADA), with leflunomide (LEF) or methotrexate (MTX), in a two year open-label study performed in clinical practice. We evaluated 96 patients with active rheumatoid arthritis undergoing therapy with ADA at the dose of 40 mg every other week, or with ETN at the dose of 50 mg/week for two years added to prednisolone (PDN) at the mean dose of 5.2±2.6 mg/day. Fifty-four of these patients were also undergoing therapy with MTX at the mean dose of 11.7±2.6 mg/week, while 42 patients were undergoing therapy with LEF at the daily dose of 20 mg. At 12 months, the analysis of variance showed an improvement of DAS28 in both groups (p<0.001), with a reduction in 33.3% of the patients in treatment with LEF and in 51.8% of the patients in treatment with MTX (p = 0.20). At 18 months, improvement was present in 33.3% of the patients in the LEF group and in 81.5% of the patients in the MTX group (p=0.001). This improvement seems to be independent of the anti-TNF-alpha agent, even if MTX produces the highest DAS28 reduction when used in association with ETN (p<0.078). We found no difference in drug discontinuation rates or in effectiveness measures between anti-TNFalpha+MTX and anti-TNFalpha+LEF. Our data showed a greater reduction of DAS28 in the MTX group and, in combination with ETN, better results after two years of therapy.

Effects of monthly intramuscular neridronate in rheumatic patients in chronic treatment with low-dose glucocorticoids.

OBJECTIVES: To assess the effects of intramuscular (im) neridronate (NE) on lumbar and femoral neck BMD and on markers of bone turnover in rheumatic patients under chronic low-dose glucocorticoids (GC) therapy. METHODS: Sixty-nine osteopoenic and osteoporotic patients, affected by rheumatic diseases and gastric or esophageal conditions which contraindicated treatment with oral bisphosphonates (BPs), were randomly assigned to: Group A (23 patients) administered with daily calcium 1 g and vitamin D 800 UI; Group B (46 patients) receiving daily calcium 1 g, vitamin D 800 UI and im NE 25 mg monthly. RESULTS: After 12 months of therapy (M12) lumbar BMD was reduced of 2.97% in Group A, and improved of 3.34% (p=0.001) in Group B; at M12, femoral neck BMD was reduced of 2.40% in Group A and improved of 1.78% in Group B (p=0.010). After 6 (M6) and 12 months of therapy, the bone resorption markers were significantly reduced in Group B: OHPr-41.64% at M6 (p<0.001) and -37.91% at M12 (p<0.001); DPD-33.4% at M6 (p<0.001) and -33.18% (p<0.001) at M12: NTX -57.08% (p<0.001) at M6 and -55.95% (p<0.001) at M12; OC-11.62% (p=0.05) at M6 and -12.62% at M12 (p=0.06); B-ALP -13.95 % at M6 (p=0.04) and -0.85% at M12 (NS). CONCLUSION: A twelve-month intramuscular NE treatment in rheumatic patients under GCs therapy improves lumbar and femoral BMD and mainly reduces the markers of bone resorption.

Correlation between atopy and hypersensitivity reactions during therapy with three different TNF-alpha blocking agents in rheumatoid arthritis.

OBJECTIVE: The use of TNF-alpha antagon-ists (infliximab, etanercept, adalimumab) has changed the course of many rheumatic diseases including rheumatoid arthritis (RA). Since their approval, some questions regarding their safety have been raised. Both acute and delayed reactions have been described. METHODS: The aim of our work was to detect if there is a different incidence of hypersensitivity reactions - infusion reactions to infliximab or injection site reactions with etanercept or adalimumab - in atopic patients versus non- atopic patients. In 90 patients (82 females, 8 males) with rheumatoid arthritis we evaluated, during the first year of therapy with three different TNF-alpha blocking agents, total serum IgE (normal value <100 KU/L) (method ImmunoCAP PHADIA) and serum specific IgE performing a qualitative multi-allergen test for inhal-ant allergens (PHADIATOP, method ImmunoCAP PHADIA). In all patients we evaluated injection site reactions (ISR) to etanercept and adalimumab - erythema, edema and itching at the site of subcutaneous administration - and infusion reactions to infliximab - hypotension/hypertension, chest pain, dyspnea, laryngospasm, fever, urticaria angioedema. RESULTS: We obtained the following results: patients with high value of tot-al IgE were 15/90 (16.6 %), patients with total IgE in normal range were 75/90 (83.4.%), reactions in patients with high total IgE were 6.7% and in patients with normal total IgE were 18.7% (p=0.255 ns). As regards serum specific IgE, patients with specific IgE were 17/90 (18.8%) patients without specific IgE were 73/90 (81.2%), reactions in patients with specific IgE were 11.8% and in patients without specific IgE were 17.8% (p=0.547 ns). Also, when the data were divided for the three groups, the differences were not statistically significant. CONCLUSION: Adverse reactions to biological agents have been categorized into five types. In hypersensitivity reactions - the Beta type reactions - an immune mechanism is suspected. Our data showed that there was no correlation between the atopic status and the incidence of hypersensitivity reactions during the first year of therapy with three different TNF-alpha blocking agents.

The economic burden of biological therapy in rheumatoid arthritis in clinical practice: cost-effectiveness analysis of sub-cutaneous anti-TNFalpha treatment in Italian patients.

Rheumatoid arthritis (RA), with a prevalence of 0.46%, is found in about 272,004 patients in Italy. The socioeconomic cost of rheumatoid arthritis in Italy in 2002 has been estimated at Euro 1,600 million. Cost-effectiveness evaluations 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. Many cost-effective studies have been based on the variation of Health Assessment Questionnaire (HAQ) in clinical trials. The objective of this study is to perform a cost-effective analysis of 86 patients with rheumatoid arthritis in therapy with adalimumab 40 mg every other week and etanercept 50 mg/week for two years in a population of patients observed in clinical practice. The group of patients in therapy with adalimumab had also taken methotrexate, mean dose 12.4+/-2.5 mg/week (22 patients) or leflunomide 20 mg/day (16 patients). The group of patients in therapy with etanercept had also taken methotrexate, mean dose 11.7+/-2.6 mg/week (24 patients) or leflunomide 20 mg/day (24 patients). Incremental costs and QALYs (quality adjusted life years) gains are calculated compared with baseline, assuming that without biologic treatment patients would remain at the baseline level through the year. Conversion HAQ scores to utility were based on the Bansback algorithm. The results after two years showed: in the group methotrexate+adalimumab the QALY gained was 0.62+/-0.15 with a treatment cost of Euro 26,517.62 and a QALY/cost of Euro 42,521.13. In the group methotrexate + etanercept the QALY gained was 0.64+/-0.26 with a treatment cost of Euro 25,020.96 and a QALY/cost of Euro 39,171.76. The result of using etanercept in association with methotrexate is cost-effectiveness with a QALY gained under the acceptable threshold of Euro 50,000. These are important data for discussion from an economic point of view when we choose a biologic therapy for rheumatoid arthritis in clinical practice.

Compared clinical efficacy and bone metabolic effects of low-dose deflazacort and methyl prednisolone in male inflammatory arthropathies: a 12-month open randomized pilot study.

OBJECTIVE: To evaluate: (i) a correct equivalence ratio of clinical efficacy between low-dose deflazacort (DFZ) and methyl prednisolone (MP); and (ii) bone metabolic effects of low-dose DFZ and MP in the treatment of male RA and PsA. METHODS: A total of 21 male patients with active RA or PsA, naive to steroid treatment were chosen for the study. Group I: 10 patients treated for 6 months with DFZ 7.5 mg, calcium, cholecalciferol and a DMARD; for the following 6 months with MP 4 mg, calcium, cholecalciferol and a DMARD. Group II: 11 patients treated for 6 months with MP 4 mg, calcium, cholecalciferol and a DMARD; for the following 6 months with DFZ 7.5 mg, calcium, cholecalciferol and a DMARD. At day 0, 90, 180, 240 and 360 evaluation of ACR improvement criteria; a blood sample for total and bone-specific ALP, calcium, phosphorus, PTH, SHBG, estradiol, ACTH, osteocalcin, LH, OPG; a sample of urine for calcium, phosphorus, creatinine and DPD. RESULTS: 13/21 patients (6/10 Group I; 7/11 Group II) reached ACR 20 at 6 months; 14/21 (7/10 Group I, 7/10 Group II) at 12 months. Only at the third month we observed in Group II vs Group I a reduction of OPG (24% vs 6%, P = n.s.); ALP (P < 0.001) and osteocalcin (P = 0.006) decreased in both groups from the third month; DPD decreased in both groups only from the sixth month (P = 0.002). CONCLUSIONS: The correct equivalence ratio of DFZ to MP is 1.875:1, and of DFZ to prednisolone 1.5:1. We found a relative prevalence of bone resorption compared to bone formation in the first 6 months of treatment. The trend of OPG requires further investigation.

[Phenobarbital rheumatism associated with gouty arthritis. Case report with 18-month follow-up]. / Associazione reumatismo gardenalico--artrite gottosa: caso clinico con follow-up di 18 mesi.

Anticonvulsivant-induced rheumatism has been described in the literature mostly in relation to phenobarbital therapy. We report the case of an 85-year-old male affected by generalized seizures and treated with phenobarbital for some months, who came to our observation on account of a long-lasting arthropathy which was diagnosed as unknown gouty arthritis. After treatment however, a clinical picture of shoulder-hand syndrome persisted: this latter disappeared after substitution of phenobarbital with phenytoin. The association of a syndrome of rheumatism induced by barbiturates with gouty arthritis has not been previously described in the literature.

Clarithromycin in rheumatoid arthritis patients not responsive to disease-modifying antirheumatic drugs: an open, uncontrolled pilot study.

OBJECTIVE: In 1996 we found by serendipity that 2 patients with rheumatoid arthritis (RA) who were taking clarithromycin (CM) to eradicate Helicobacter pylori experienced a regression of their RA symptoms. Following this observation, we tested the hypothesis that this reduction in symptoms could have been caused by CM administration. METHODS: We performed a 6-month, open, uncontrolled pilot study on 18 patients (14 females and 4 males, mean age 62 yrs.) with RA who had previously received DMARDs (mean 2.6) and discontinued the treatment at least one month earlier because lack of efficacy or severe side effects. Patients were treated with CM at the dose of 500 mg twice per day for the first 10 days, followed by a daily maintenance dose of 250 mg twice per day. RESULTS: 4/18 patients did not complete the treatment, 2/18 were not responsive to the treatment and 2/18 discontinued the treatment. Following ACR criteria the improvement was: 10 patients ACR 20; 6 patients ACR 50; and 2 patients ACR 70. The remaining 4 patients did not reach ACR 20 since either the number of tender or swollen joints was not to the level required. Reductions in PGE2 and soluble phospholipase A2 plasma levels were closely related to CM plasma levels. CONCLUSIONS: Ourfindings suggest that CM treatment can be beneficial in those patients who are not responsive to or cannot tolerate DMARDs. No definitive conclusions can be drawn based on the present study, due to the small sample size involved.