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The nephrologist deals with the management of patients with rheumatic disease, both diagnostically and therapeutically. He must determine whether the renal pathology is related to the rheumatologic disease, mostly through the use of the renal biopsy. In the second case, he must know the nephrotoxic potential of the drugs prescribed and adjust their use to the degree of renal impairment. This task is made difficult by the absence of controlled clinical trials regarding their use on patients with renal insufficiency or on chronic dialysis. For this reason, the prescription will have to take into account the pharmacokinetics of the drugs. Kidney failure can affect the metabolism of antirheumatic drugs determining their accumulation, which can lead to increased toxicity, either renal or systemic. On the other hand, dialysis can cause excessive drug removal, leading to sub-therapeutic pharmacological effects and to the need for additional doses. In this brief review, we will consider the nephrotoxic effects of some important drugs used in rheumatology and examined individually, with specific reference to rheumatoid arthritis: methotrexate, leflunamide, hydroxychloroquine, cyclosporine, biological DMARDs. In the past, therapeutic success in rheumatic diseases associated with kidney impairment was severely limited by the well- known nephrotoxicity of drugs such as gold salts, D-penicillamine, NSAIDs, COX-2 inhibitors. Although generally effective, they are contraindicated in case of kidney failure. Biologic therapies have recently opened new therapeutic perspectives. Nevertheless, it is worth stressing how our knowledge of their action is still incomplete and this may result in exposure to immune-mediated renal disease.

The introduction of biological agents has been a major turning-point in the treatment of rheumatic diseases, particularly in rheumatoid arthritis. This review describes the principle milestones that have led, through the knowledge of the structure and functions of nucleic acids, to the development of production techniques of the three major families of biological agents: proteins, monoclonal antibodies and fusion proteins. A brief history has also been traced of the cytokines most involved in the pathogenesis of inflammatory rheumatic diseases (IL-1 and TNF) and the steps which have led to the use of the main biological drugs in rheumatology: anakinra, infliximab, adalimumab, etanercept and rituximab.

The pharmacological treatment of pain has very ancient origins, when plant-derived products were used, including mandrake extracts and opium, a dried latex obtained from Papaver somniferum. In the XVI and XVII centuries opium came into the preparation of two compounds widely used for pain relief: laudanum and Dover's powder. The analgesic properties of extracts of willow bark were then recognized and later, in the second half of the XIX century, experimental studies on chemically synthesized analgesics were planned, thus promoting the marketing of some derivatives of para-amino-phenol and pyrazole, the predecessors of paracetamol and metamizol. In the XX century, nonsteroidal anti-inflammatory drugs were synthesized, such as phenylbutazone, which was initially considered primarily a pain medication. The introduction on the market of centrally acting analgesics, such as tramadol, sometimes used in the treatment of rheumatic pain, is quite recent.

The discovery of aspirin, an antipyretic, anti-inflammatory and analgesic drug, undoubtedly represents a milestone in the history of medical therapy. Since ancient times the derivatives of willow (Salix alba) were used to treat a variety of fevers and pain syndromes, although the first report dates back to 1763 when the English Reverend Edward Stone described the effect of an extract of the bark willow in treating malaria. In the XIX century many apothecaries and chemists, including the Italian Raffaele Piria and Cesare Bertagnini, developed the biological processes of extraction and chemical synthesis of salicylates, and then analyzed their therapeutic properties and pharmacokinetic and pharmacodynamic characteristics. In 1899 the Bayer Company, where Felix Hoffmann, Heinrich Dreser and Arthur Eichengrün worked, recorded acetyl-salicylic acid under the name "Aspirin". In the XX century, besides the definition of the correct applications of aspirin in the anti-rheumatic therapy being defined, Lawrence L. Crawen identified the property of this drug as an anti-platelet agent, thus opening the way for more widespread uses in cardiovascular diseases.

Objective: To develop a set of national evidence-based recommendations for the use of Methotrexate (MTX) in daily clinical practice., Methods: A panel of 37 Italian Rheumatologists reviewed 10 international recommendations formulated during the "3E (Evidence, Expertise, Exchange) initiative" for the year 2007-8, following a systematic literature search in Medline, Embase, Cochrane Library, and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts and the revision of selected papers and the appraisal of Oxford levels of evidence. Moreover, the same panel by the same methodology formulated further 5 recommendations on topics previously selected by Italian representatives to 3E initiative. The agreement about the set of proposed recommendations was stated by a consensus process and the potential impact on clinical practice was assessed., Results: International Recommendations were analysed and changed when appropriate. In addition, 5 national recommendations were developed by identifying 6371 references, selecting and evaluating the 29 ones satisfying Evidence Based Medicine principles., Conclusions: A set of 15 national recommendations for the use of MTX in daily clinical practice was developed. These recommendations are evidence-based and integrate the expertise of a large panel of Italian rheumatologists.

The beneficial effects of omega-3 polyunsaturated fatty acids have been widely described in the literature in particular those on cardiovascular system. In the last decade there has been an increased interest in the role of these nutrients in the reduction of articular inflammation as well as in the improvement of clinical symptoms in subjects affected by rheumatic diseases, in particular rheumatoid arthritis (RA). Nutritional supplementation with omega-3 may represent an additional therapy to the traditional pharmacological treatment due to the anti-inflammatory properties which characterize this class of lipids: production of alternative eicosanoids, reduction of inflammatory cytokines, reduction of T-lymphocytes activation, reduction of catabolic enzymes activity. The encouraging results of dietetic therapy based on omega-3 in RA are leading researchers to test their effectiveness on patients with other rheumatic conditions such as systemic lupus erythematosus and ankylosing spondylitis. Nutritional therapy based on food rich in omega-3 or on supplementation with fish oil capsules, proved to be a valid support to he treatment of chronic inflammatory rheumatic diseases.

Some important discoveries in the history of rheumatology happened during war periods. It is well known that arthritis associated with conjunctivitis and urethritis, following dysenteric episodes, has been described during the First World War from the German Hans Reiter and, nearly contemporarily, from the French Nöel Fiessinger and Edgar Leroy. Less known is instead the fact that the first cases of sympathetic algoneurodystrophy have been reported by the American Silas Weir Mitchell in soldiers wounded by fire-arms, during the Civil War of Secession. Other war episodes have been crucial for the development of some drugs now abundantly applied to the care of rheumatic diseases. The discovery of therapeutic effects of immunosuppressive agents, in fact, happened as an indirect consequence of the use of poison gas, already during the First World War (mustard gas), but above all after an episode in the port of Bari in 1943, where an American cargo boat was sunk. It had been loaded with a quantity of cylinders containing a nitrogenous mustard, whose diffusion in the environment provoked more than 80 deaths owing to bone marrow aplasia.Moreover, the history of the cortisone shows a strict link to the Second World War, when Germany imported large quantities of bovine adrenal glands from Argentina, with the purpose of producing some gland extracts for the Luftwaffe aviators, in order to increase their performance ability.

The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some autoinflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.

Glucocorticoids (GC) are diffusely used to treat a wide variety of inflammatory and autoimmune disorders, including rheumatic diseases. GC-induced osteoporosis (GIO) is the most common and serious side-effect for patients receiving GC. Loss of bone mineral density (BMD) is greatest in the first few months of GC use; fracture (Fx) risk is significantly increased at the spine and hip on doses even as low as 2.5 mg of prednisolone daily; Fx risk increases rapidly from the onset of therapy and, for a given BMD, is higher in GIO than in postmenopausal OP. General measures to reduce bone loss include use of the lowest effective dose; consideration of alternative routes of administration; adequate calcium and vitamin D supplementation. Today, results from large randomised controlled clinical trials provide evidence that bone loss and Fx may be prevented through the use of bone sparing agents (hormone therapy, bisphosphonates, PTH 1-34). Bisphosphonates (alendronate, risedronate) are first-choice therapy for the prevention and treatment of GIO; patients at high risk for Fx, for example those in post-menopausal status or aged > or =65 years and those with a prior fragility Fx, should be advised to start bone-protective therapy at the time of starting GC. Due to the prevalence of GC use, it is imperative that there be a greater awareness of GIO and of therapies that may be offered to patients both for prevention and treatment.

Objective: To analyse TNF-α antagonists (infliximab, etanercept e adalimumab) side effects published in the literature., Methods: Review of published studies on this matter., Results: The main side effects reported include severe infections (even though such a risk is increased per se in RA patients), possible reactivation of a previous tuberculosis, development of opportunist germs infections (mainly those with granulomas development as Aspergillus, Cryptococcus e Histoplasma). During therapy with both infliximab and etanercept development and reactivation of demyelisating diseases have been described, sometimes associated with permanent disability. Congestive heart failure, even in the absence of predisposing risk factors, development of lymphoma, mainly non-Hodgkin, and few cases of pancytopenia with hypocellular bone marrow have also been reported., Conclusions: Since comparison studies on the 3 TNF-α antagonists have not been performed yet, at present it is not possible to suggest using one drug out of the three in different clinical conditions; undoubtedly, the safety profile represents a major criterion to choose the more appropriate drug in the daily clinical practice.

Objective: To provide an analysis and a guide tool in using TNFα-antagonists in the current clinical practice., Methods: Review of the literature on the differences among the three TNFα-antagonists in terms of molecular structure, mechanism of action, pharmacokinetics, effects on the immune and neuroendocrine systems, and therapeutic indications., Results and Conclusions: Unfortunately, results of direct comparison studies are lacking. One could obviate this problem by performing statistical-mathematical extrapolations, but there are very few and very small-sized published experimental evidences.

The article describes the EMEA approved indications of TNFα antagonists (adalimumab, etanercept and infliximab) in the various clinical conditions and their increasing use in diseases other than those already approved. The Authors discuss their use during pregnancy, the efficacy of a second TNFα antagonist after failure or side effects development with a previous biologic agent and the different efficacy of the various agents depending on the different clinical conditions.

In the article, the literature on the effects of TNFα-antagonists (etanercept, infliximab and adalimumab) on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn's disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo-pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.

The commercially available inhibitors of TNF are constituted by two classes of molecules: the soluble receptors (Etanercept: Amgen Inc. Wyeth) and the monoclonal antibodies (Adalimumab: Abbott Laboratories and Infliximab: Centocor, Inc.). The differences in their molecular structure, mechanism of action, pharmacokinetics (PK) and pharmacodynamics (PD) are discussed, along with the differences concerning dose, administration regimens, drug concentrations and pharmacological interactions. In order to explain the clinical differences observed when these agents are used in the "real world", which can arise from the respective PK characteristics (kinetics, route and frequency of administration, type of TNF binding, effects on cytokines) and PD responses and peculiar mechanisms of action, with distinctive immune function (LFTα inactivation; apoptosis induction, TNF immunoprecipitation, C1q binding and CDC induction; Fcγ cross-linking and ADCC induction), the dynamics of interaction of the two classes of neutralizing molecules with TNF, and the ability in restoring TNF homeostasis, are outlined.

Objective: We have developed a standardized technique for intra-articular injection of the hip joint with the purpose of extending routine intra-articular injection of hyaluronans and steroids to the hip, as commonly used in the knee. The purpose of this study was to examine the safety of this technique in an extended series of patients., Methods: A 7 MHz linear or 3.5 MHz convex transducer was used with a sterilized biopsy guide attached. Intra-articular (IA) injection was performed by inserting into the biopsy guide a 20 gauge needle with the anterosuperior approach. Then, using biopsy real-time guidance software, the needle was advanced into the anterior capsular recess, at the level of the femoral head., Results: The standardised technique was used to inject 97 patients (114 hips) with 185 injections of either steroid/local anaesthetic (10) or hyaluronan (175) over a three-year period. The treatment was well tolerated with few, and exclusively local, side effects. No systemic side effects or joint infections were observed in our study. The colour Doppler vision allowed us to avoid injecting blood vessels. In all cases direct visualization of needle introduction and progression into the articular space was shown by on-screen guidance. Ultrasound guidance is more economic and faster in comparison to the TC or fluoroscopic guidance. Contrary to TC or fluoroscopic techniques ultrasound does not require use of radiations or iodized contrast., Conclusion: Our data suggest that the administration of hyaluronans or steroids with ultrasound-guided intra-articular injection is a safe technique for treatment of rheumatic diseases of the hip.

The Authors summarize the current knowledge on a new class of nonsteroidal anti-inflammatory drugs (NSAIDs), the coxib (celecoxib and rofecoxib), in the treatment of rheumatic diseases. Celecoxib and rofecoxib are selective cyclooxygenase-2 (COX-2) inhibitors which possess the same anti-inflammatory and analgesic activities, but a better gastric tolerability compared to the non-selective COX-1 and COX-2 inhibitors. The Authors also report other possible therapeutic effects of these NSADIs as evidenced by the more recent data of the literature. Celecoxib seems to reduce the incidence of new polyps in patients with familial adenomatous polyposis. It has been suggested the use of celecoxib as a protective drug against the development of colorectal cancer. Other (neoplastic) or pre-neoplastic conditions, such as bladder dysplasia, Barret esophagus, attinic keratosis and Alzheimer's disease seem to have benefit from this class of drugs.

Sidenham's chorea represents one of the gold standards of rheumatic fever. Its identification however has recently become more difficult, owing to the progressive decrease of rheumatic fever itself. Nevertheless this pathology disturbing both the child and the family, easily dominated by a suitable therapy, is still topical: we report 8 cases, 5 males and 3 females running from 7 to 13 years of age, admitted to our pediatric Division from 1988 to 1992, with typical symptomatology and fair clinical evolution.

A study was performed with 60 patients, affected by acute phase rheumatological pathology, in order to determine the optimum posology of ST-679 administered orally. The 60 patients were divided into 4 groups: 3 treated with ST-679 at different dosages (group 1 = 600 mg/die; group 2 = 1200 mg/die; group 3 = 1800 mg/die) and one with placebo (group 4 = 600 mg/die). The highest dosage employed (1800 mg/die) performs an excellent therapeutical activity which is equivalent to that at the 1200 mg in reducing pain symptomatology, but on the average less tolerated. The 600 mg dosage was less efficacious with respect to the two higher doses.

We describe a case of a 59-year-old white woman, that first developed a myasthenia gravis picture, then palindromic rheumatism and, in the end, systemic lupus erythematosus. We have searched in the literature the common features and the differences between myasthenia gravis and systemic lupus erythematosus. In this report we emphasize the possible connection between palindromic rheumatism and autoimmune diseases.

Preliminary data concerning the efficacy and tolerability of tenoxicam in a large, multicenter Italian study are presented. In many centres 625 patients (31% of the total) have been evaluated: 283 patients with osteoarthrosis and 342 with extra-articular rheumatism completed the study. Efficacy of tenoxicam (20 mg/die) was stated as equivalent or superior to reference drugs (diclofenac 100 R, piroxicam 20 mg). Tolerability profile has been generally good; tenoxicam, in particular showed the lowest incidence of side effects (7.4%).

Sulphasalazine (SLZ) has proved to be a drug effective in inducing clinical improvement or remission in chronic inflammatory rheumatic diseases (other than inflammatory bowel diseases) such as rheumatoid arthritis (RA) and some seronegative spondyloarthropathies, in a fashion similar to that of long-acting, second-line drugs in RA. Several clinical studies agree upon the efficacy of the compound employed at a dose of 2-3 g/day and upon the incidence of side effects, which appear to be equivalent to or lower than those related to traditional disease-modifying drugs employed in RA. The following points should be clarified and developed with regard to the use of SLZ in chronic rheumatic diseases: main mechanism(s) of action, improvement of therapeutic strategy (i.e.: combined treatments, maintenance therapy), prevention and control of main side effects, and its preferential use or limits in the management of a larger number of inflammatory rheumatic diseases.

One case of myocardial infarction and one case of coronary insufficiency, observed in women treated with oral contraceptives, are presented. Pathogenetic hypotheses are put forward and stress is laid on the necessity of evaluating risk factors as well as carrying out the various hemogenic tests in these patients.

Nimesulide is a new non-steroidal anti-inflammatory drug which seems to be characterized by a low inhibitory action on prostaglandin synthesis and a high inhibitory action on oxygen free radicals production. The aim of this trial was to determine the effect of Nimesulide on degenerative joint disease and on non-articular rheumatism. One hundred and forty, 64 females and 76 males aged 51.9 +/- 1.2 years, affected with osteoarthritis or non-articular rheumatism (fibromyalgia, periarthritis, tendinitis, tenosynovitis, bursitis and enthesitis) were studied. Nimesulide was administered at a daily dosage of 200 mg. A significative improvement in the clinical parameters studied was observed in all the patients, but a more remarkable progress was noted in the group with non-articular rheumatism. The incidence of adverse reactions was irrelevant: 2 patients complained of epigastralgia that subsided reducing the daily dosage to 100 mg.

An open trial was carried out in 100 outpatients suffering from osteoarthritis (52 subjects) or extra-articular rheumatic disorders (48 subjects). Treatment consisted in topical application 3 times daily of an experimental product, BPAA gel, with 3% of active substance, for 2 weeks. During treatment the use of steroidal and non-steroidal analgesic and antiinflammatory agents or of any other drug apt to interfere with the parameters of evaluation was carefully avoided. Patients cooperated actively in subjective evaluation of pain parameters (Visual Analogue Self-rating Scale) which was used to integrate objective evaluation. Treatment response was very favorable, the drug proving effective in 83% and fairly effective in 5.7% of patients with osteoarthritis (total 88.7%). The corresponding figures for patients with extra-articular rheumatic disorders were 83.4% and 6.2% (total 89.0%). No local or systemic side-effects were observed in any of the 100 patients, nor did laboratory tests reveal any untoward actions of the drug.

The results of a set of experiments conducted on a new non-steroid antirheumatic preparation--pyrasanone (Carudol)--are presented and its indications in the general management of the disease are noted. The pharmacokinetics and therapeutic efficacy of the new drug are described. Statistical analysis showed it to be more effective than hexahydropyrazine, diphenylbutazone, indomethacin and oxyphenbutazone. A basic therapeutic approach is suggested in accordance with the pharmacodynamic aspects of the drug and the results observed in a clinical trial on 719 subjects. Pyrasanone has low toxicity and is well tolerated. Due caution in the administration of antirheumatic drugs should nevertheless be maintained during its use.

Fifty outpatients suffering from rheumatoid disorders were treated with proglumetacin. Efficacy was classified as "good" or "very good" in 80% of cases. Besides this considerable efficacy, a tolerance classified as "good" or "very good" was observed in 86% of patients.

The antalgic activity of a newly characterized NSAID (cinnoxicam) was evaluated by cutaneous sensimetry. A precocious and significant increase in pain threshold was demonstrated by the algometric data observed after oral administration of one tablet of the drug under examination in both healthy volunteers and in rheumatic patients.