Perspectivas con dianas para el tratamiento de la artritis reumatoide / Perspectives with targets for the treatment of rheumatoid arthritis

La artritis reumatoide se clasifica como una enfermedad articular autoinmune crónica poliarticular sistémica que afecta principalmente a manos y pies. El objetivo de este trabajo es mostrar información publicada que contribuye a direccionar el manejo de la artritis reumatoide con nuevos fármacos, a partir del conocimiento de aspectos novedosos relacionados con la fisiopatología y los avances recientes sobre un grupo importante de dianas para el tratamiento de esta enfermedad. Las modificaciones epigenéticas pueden regular la expresión génica sin alterar la secuencia del ADN. La regulación de los ARN no codificantes (ncRNA), la metilación del ADN, la metilación del ARN y las modificaciones de las histonas se consideran los principales mecanismos de las regulaciones epigenéticas. Numerosas investigaciones han establecido que varias anomalías en estos mecanismos terminan en el desarrollo de la AR. Este trabajo resume nuevas dianas, que incluyen proteínas, pequeños metabolitos moleculares y reguladores de la epigenética. Son dianas moleculares prometedoras para el descubrimiento de fármacos que alivien la aparición de enfermedades y resuelvan la falta de respuesta y las respuestas parciales, así como los efectos adversos de los FARME actuales. Es innegable que aún se necesitan mayores esfuerzos para definir con mayor precisión las vías de señalización subyacentes afectadas por estas moléculas recién descubiertas y para desarrollar métodos de terapia apropiados(AU)

Rheumatoid arthritis is classified as a systemic polyarticular chronic autoimmune joint disease that mainly affects the hands and feet. The objective of this work is to show published information that contributes to directing the management of RA with new drugs. Epigenetic modifications can regulate gene expression without altering the DNA sequence. Regulation of non-coding RNAs (ncRNAs), DNA methylation, RNA methylation, and histone modifications are considered the main mechanisms of epigenetic regulations. Numerous investigations have established that various abnormalities in these mechanisms lead to the development of RA. This work summarizes new targets, including proteins, small molecular metabolites and regulators of epigenetics. They are promising molecular targets for drug discovery to alleviate disease onset and resolve non-response and partial responses, as well as adverse effects of current DMARDs. It is undeniable that further efforts are still needed to further define the underlying signaling pathways affected by these newly discovered molecules and to develop appropriate therapy methods(AU)

Lost in Translation? Cortisone and the Treatment of Rheumatoid Arthritis in Britain, 1950-1960. [corrected].

Cortisone, initially known as 'compound E' was the medical sensation of the late 1940s and early 1950s. As early as April 1949, only a week after Philip Hench and colleagues first described the potential of 'compound E' at a Mayo Clinic seminar, the New York Times reported the drug's promise as a 'modern miracle' in the treatment of rheumatoid arthritis (RA). Given its high profile, it is unsurprising that historians of medicine have been attracted to study the innovation of cortisone. It arrived at the end of a decade of 'therapeutic revolutions', kicked off by penicillin transforming the treatment of bacterial infections and ending with hopes of a revolution in the treatment of non-infectious, chronic inflammatory diseases. Despite these studies of cortisone's introduction, few historians have taken the story forward and considered how cortisone was adopted and adapted into clinical practice. This article tells the longer of how the drug and its derivatives were taken from research laboratories and integrated into clinical practice; what has in recent decades become known as translational medicine (TM). In exploring cortisone's first decade in Britain, we focus specifically on its role in the treatment of RA. Our approach is always to consider cortisone's use in the context of other treatments available to clinicians, and at local and national institutional settings. We do not discuss the many other therapeutic uses of cortisone, which ranged for topical applications for skin diseases to the management of cancers, especially childhood leukaemia, nor do we discuss its close analogue ACTH-AdenoCorticoTropic Hormone. We think there are lessons in our study for TM policies today.

On the history of gout: paleopathological evidence from the Medici family of Florence.

OBJECTIVES: Throughout history, gout has been referred to as the "disease of the kings", and has been clearly associated with the lifestyle of the aristocratic social classes. According to the written sources, several members of the famous Medici family of Florence suffered from an arthritic disease that contemporary physicians called "gout". A paleopathological study carried out on the skeletal remains of some members of the family, exhumed from their tombs in the Church of San Lorenzo in Florence, offered a unique opportunity to directly investigate the evidence of the arthritic diseases affecting this elite group. METHODS: The skeletal remains of several members of the family were examined macroscopically and submitted to x-ray investigation. RESULTS: The results of the study allowed us to ascertain that the so-called "gout of the Medici" should be considered the clinical manifestation of three different joint conditions: diffuse idiopathic skeletal hyperostosis, rheumatoid arthritis and uratic gout. In particular, uric acid gout was diagnosed in the Grand Duke Ferdinand I (1549-1609). Recently, a new case of this disease was diagnosed in Anton Francesco Maria (1618-1659), a probable illegitimate member of the family. CONCLUSIONS: With this new case, uratic gout was observed in 2 out of 9 adult males, leading to suppose that the disease should have been a common health problem within the family. The aetiology of the disease has to be searched in environmental factors, since both historical and paleonutritional studies demonstrated that the diet of this aristocratic court was rich in meat and wine.

Landmark papers on the discovery of methotrexate for the treatment of rheumatoid arthritis and other systemic inflammatory rheumatic diseases: a fascinating story.

This review highlights the story of how methotrexate (MTX), a drug discovered for the treatment of childhood leukemia, became the mainstay of treatment and the standard-of-care for rheumatoid arthritis (RA) and was also found useful for several additional related rheumatological diseases. As against several synthetic disease-modifying antirheumatic drugs (csDMARDs) for treating RA that were discovered serendipitously, the use of low-dose MTX (LD-MTX) was based on sound reasoning and astute observations made in the 1940s and 1950s. The difference between high-dose MTX (HD-MTX) used in the treatment of childhood leukaemia and other malignancies as against LD-MTX used in rheumatology is emphasized.

Approach to the diagnosis of unusual carpal ankylosis from ancient Egypt.

OBJECTIVES: Carpal fusion is not an uncommon finding in archaeological bones. The majority of cases are due to inflammatory or infectious diseases and those are usually associated with other major alterations in the skeleton. METHODS: Two distinct individual cases, both adult females recovered from the Necropolis of Sharuna in the Middle Egypt from the Ptolemaic Period (IV to I BC) are presented in this study. Specimen 4323/1 shows a fusion of the scaphoid, lunate and triquetral bones in the right wrist. Specimen 4323/2 is a very rare fusion of a dysplastic lunate bone with the radius in the left wrist. In the proximal end of that left wrist, two possible remains of the flattened scaphoid and triquetral bones are also present. RESULTS: A differential diagnosis of both abnormalities as well as broad research into similar paleopathological cases were carried out: the most probable diagnosis for the specimen 4323/1 is an uncommon carpal coalition of three bones from the same row; the diagnosis of the specimen 4323/2 is more dubious with both rheumatoid arthritis and septic arthritis being strong candidates. CONCLUSIONS: In archaeological remains, carpal fusion should be thoroughly studied in order to ensure an accurate differential diagnosis.

[Pharmacotherapy for rheumatoid arthritis in the early 21st century: Russian and international experience].

The paper summarizes the data of international and Russian studies concerning current approaches to the pharmacotherapy of rheumatoid arthritis. Particular emphasis is placed on the substantiation of the treat-to-target concept, on the efficacy and safety of genetically engineered biological agents, including the inhibitors of tumor necrosis factor, interleukin-6 receptors, T-lymphocyte co-stimulation, and anti-B-cell therapy.

The "gout of the Medici": making the modern diagnosis using paleopathology.

Documentary sources show that painful joint disease afflicted several members of the Medici family, which dominated Renaissance Florence in Italy. The term frequently reported in contemporary archives to indicate these morbid episodes is "gout." Paleopathology allows us to verify the nosological information obtained from the written documents and to clarify the nature of the rheumatological condition that afflicted the Medici. A paleopathological study carried out on the skeletal remains of several members of the Medici family buried in the basilica of S. Lorenzo in Florence demonstrated that the "gout" of the Medici was truly a uric acid gout only in Ferdinand I (1549-1609), whose left foot showed peculiar lesions. Genetic and environmental factors, with particular regard to diet, may have been involved in the etiology of this disease, which in Ferdinand was associated with diffuse idiopatic skeletal hyperostosis (DISH). DISH was observed also in the column of Cosimo the Elder (1389-1464) and Cosimo I (1519-1574); a link between the incidence of DISH and high social status, especially in terms of lifestyle and nutritional patterns, has been suggested and the present study seems to further confirm this association. Finally, rheumatoid arthritis (RA) was diagnosed in Cosimo the Elder, Piero "the Gouty" (1416-1469) and Cardinal Carlo (1596-1666); as for Carlo, macroscopic and radiological findings were supported by molecular results which revealed that he was bearing the specificity HLA-DR4 predisposing to RA. The coexistence of DISH and RA attested in Cosimo the Elder can be interpreted as coincidental. In conclusion, the term "gout" as used in Renaissance texts has to be regarded as the clinical manifestation of a number of different joint diseases. In the case of the Medici family in Florence, these included DISH, rheumatoid arthritis and uric acid gout.

Niki de Saint Phalle's lifelong dialogue between art and diseases: psychological trauma of sexual abuse, transient selective IgA deficiency, occupational exposure to toxic plastic material, chronic lung disease, rheumatoid arthritis.

The French artist Niki de Saint Phalle (1930-2002) is one of the most famous female painter and sculptor of the 20th century. Her eventful live was full of emotional and physical burdens such as abuse by the father as a adolescent, early separation from family, nervous collapse, turbulent relationship with the artist Jean Tinguely, and last not least serious diseases. The psychological trauma of sexual abuse together with a "nervous breakdown" years later was the start of a life as an artist and is also a key to her art of the early years. She was affected from rheumatoid arthritis (RA) and was treated over 20 years with prednisolone and antimalarials leading to a good functional outcome and limited erosions of the wrist joint. Additionally, she had lifelong pulmonary disorders finally leading to death, which she attributed to polyester, the material used for her sculptures. An analysis of medical documents collected by her and provided by treating physicians gives another surprising explanation: selective IgA deficiency with multiple recurrent respiratory infections, asthma, milk intolerance, autoimmune thyroiditis, and RA compatible with hypogammaglobulinemia. Very unique in case of Niki de Saint Phalle is that IgA deficiency was transient. Nevertheless, it may be possible that the occupational exposure with art materials (polystyrene, polyester) has contributed in part or temporarily to her health problems. Altogether, her enormous artistic productivity represents an outstanding example of creative coping with RA and other lifelong health problems.

Great artists with rheumatoid arthritis. What did their disease and coping teach? Part II. Raoul Dufy and Niki de Saint Phalle.

Raoul Dufy (1877-1953) and Niki de Saint Phalle (1930-2002) were 2 famous artists who suffered from rheumatoid arthritis (RA). Both artists represent an additional outstanding example of successful coping with RA in former times when, for the first time, corticosteroids were available, but nevertheless treatment was very limited in the pre-biological era. Dufy was one of the earliest patients with RA who received corticosteroids and regained his creativity to paint for a few additional years, but finally he died of massive intestinal hemorrhages, the adverse event of the combination of corticosteroid plus aspirin. Niki de Saint Phalle, a self-taught French painter and sculptor, was one of the most significant and unconventional female artists of the 20th century. Her eventful life was full of emotional burdens and lifelong lung disease in addition to RA. Niki de Saint Phalle came out from each physical and emotional crisis with new forces and new artistic ideas. Interestingly, it has been suggested that the occupational exposure to colors contributed to the development of RA in artists, which used significantly more bright and clear colors based on toxic heavy metals such as Renoir and Dufy. Moreover, these 2 were cigarette smokers, a recently described risk factor for developing RA and increasing the severity once it does develop. Niki de Saint Phalle produced her sculptures made of plastic material without protection while she assumed that exposition to polyester and toxic fumes of polystyrene caused severe damage to her lungs, resulting in recurrent health problems.

Rheumatoid arthritis in Cardinal Carlo de' Medici (1595-1666): a confirmed macroscopic, radiologic and molecular diagnosis.

OBJECTIVES: The paleopathological study of the skeletal remains belonging to Cardinal Carlo de' Medici (1595-1666), son of Ferdinando I (1549-1609) and Cristina of Lorena (1565-1637), has been presented previously. A diagnosis of Klippel-Feil syndrome, tuberculosis and a polyarthopathy, interpreted as rheumatoid arthritis, was suggested. A revision of this case based on the analysis of the historical documents and of some radiological images of Carlo's bones has been proposed recently; according to the Authors, the Cardinal was affected by the 'Medici syndrome', a combined Psoriatic-DISH arthropathy. This revision offers us the opportunity to discuss this complex case, comparing different points of view, and to present the results of the molecular analyses carried out on Carlo's bone samples. We looked for the genetic risk factors of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). We also searched for the primary candidate genes of RA and PsA, i.e. DR4 or DR1 and Cw6 or DR7 respectively, the latter predisposing also for psoriasis. METHODS: An original molecular protocol was applied to achieve an aDNA uncontaminated by exogenous sources and almost intact, starting from one of the Cardinal's rib pieces. The allele risk factors for both diseases were identified by PCR-SSP assay as HLA genotyping methodology. RESULTS: Our data assigned Carlo the genotype DRB1*04/*11 for HLA-DRB locus and Cw*04/*12 for HLA-C locus. CONCLUSIONS: Since Carlo was infected by M. tuberculosis during infancy and was carrying the DR4 variant but not the Cw6, he surely had a predisposition to RA, not to PsA and/or psoriasis. The diagnosis of RA is thus confirmed.

[A short history of anti-rheumatic therapy - VI. Rheumatoid arthritis drugs]. / Piccola storia della terapia antireumatica - VI. I farmaci dell'artrite reumatoide.

The treatment of rheumatoid arthritis traditionally includes symptomatic drugs, showing a prompt action on pain and inflammation, but without any influence on disease progression, and other drugs that could modify the disease course and occasionally induce clinical remission (DMARDs or disease modifying anti-rheumatic drugs). This review describes the historical steps that led to the use of the main DMARDs in rheumatoid arthritis, such as gold salts, sulphasalazine, chloroquine and hydroxychloroquine, D-penicillamine, and other immunoactive drugs, including methotrexate, azathioprine, cyclosporin and leflunomide. The historical evolution of use of these drugs is then discussed, including the strategy of progressive ("therapeutic pyramid") or of more aggressive treatment, through the simultaneous use of two or more DMARDs ("combination therapy").

[History of gold--with danish contribution to tuberculosis and rheumatoid arthritis]. / Guld i medicinens tjeneste--Med traek af dansk indsats ved tuberkulose og reumatoid artrit.

Gold has a long history as a therapeutic agent, first as gold particles and colloidal gold, then as a soluble salt made by the alchemists, and potable gold was recommended almost as a panacea against different diseases. Gold compounds were introduced in the treatment of tuberculosis, based initially on the reputation of Robert Koch, who found gold cyanide effective against Mycobacterium tuberculosis in cultures. Although several investigations of gold salts showed no convincing effect in experimental tuberculosis in guinea pigs, the idea of using gold compounds as chemotherapy was furthermore encouraged from the work of Paul Ehrlich with arsenicals. The enthusiasm and the craving desperately for a remedy for tuberculosis forced Danish physicians, in the mid-1920s to treat tuberculosis with Sanocrysin (gold sodium thiosulfate). Professor Holger Møllgaard, in collaboration with the clinicians the professors Knud Secher and Knud Faber, was the theoretical promoter of the project. He recommended sanocrysin-antiserum therapy, since sanocrysin caused serious reactions in tuberculosis animals, possible by releasing toxins from tubercle bacilli "killed" by sanocrysin. However the enthusiastic response to sanocrysin in Europe declined along by controlled trials and reports on toxicity in the 1930s. The belief that rheumatoid arthritis was a form of tuberculosis caused a renaissance in chrysotherapy. In France Jacques Forestier obtained encouraging results in the treatment of rheumatoid arthritis with myochrysine and other gold salts, and he pointed out the disease modifying effect of chrysotherapy. In Denmark Knud Secher, who was the clinical initiator of Sanocrysin therapy in tuberculosis, now became the founder of chrysotherapy in rheumatoid arthritis. Although new potential agents are now taking over in the treatment of arthritis, it is still believed, that there is a place for the chrysotherapy. However a new future for gold, in the form of nanoparticles, appears on the horizon, especially in the imaging, diagnostics and therapies of cancer.

Methotrexate: from its introduction to non-oncologic therapeutics to anti-TNF-α.

The history of the rheumatologic use of methotrexate until the 1990s will be reviewed, beginning with its pharmacology, with the focus on rheumatoid arthritis (RA). The insufficient availability of cortisone in the 1950s as well as the early recognition of its potential toxicity stimulated searches for alternative anti-inflammatory drugs. Two related derivatives of folic acid, aminopterin and amethopterin (MTX,) were found to give rapid symptomatic relief in cases of psoriasis vulgaris and psoriatic arthritis. For several years MTX was used primarily to treat psoriasis, and the dermatologic treatment protocols came to be used by rheumatologists. Giving MTX weekly rather than daily was found to diminish the risk of toxic effects. MTX became favoured over cyclophosphamide because of its lack of carcinogenicity, and although azathioprine lacked the hepatotoxicity of MTX, its anti-rheumatic effects were considered to be somewhat weaker. Although trials of MTX for the treatment of severe RA began in the 1960s, the first placebo-controlled study of MTX in RA was reported in 1985 and a comparison with Myochrysine in 1987. MTX has replaced gold compounds because it has been found to be more rapidly effective and better tolerated. The mechanisms of its anti-rheumatic effects remain incompletely explained, as are explanations of instances of its failure. Its recent use in combination with anti-TNFα agents appears to be another therapeutic advance.

Interleukin 6 in autoimmune and inflammatory diseases: a personal memoir.

In this review, the author discusses the research that led to the identification and characterization of interleukin 6 (IL-6), including his own experience isolating IL-6, and the roles this cytokine has on autoimmune and inflammatory diseases. The cDNAs encoding B-cell stimulatory factor 2 (BSF-2), interferon (IFN)-beta2 and a 26-kDa protein were independently cloned in 1986, which in turn led to the identification of each. To resolve the confusing nomenclature, these identical molecules were named IL-6. Characterization of IL-6 revealed a multifunctional cytokine that is involved in not only immune responses but also hematopoiesis, inflammation, and bone metabolism. Moreover, IL-6 makes significant contributions to such autoimmune and inflammatory diseases as rheumatoid arthritis (RA).IL-6 activates both the STAT3 and SHP2/Gab/MAPK signaling pathways via the gp130 signal transducer. F759 mice, which contain a single amino-acid substitution in gp130 (Y759F) and show enhanced STAT3 activation, spontaneously develop a RA-like arthritis as they age. F759 arthritis is dependent on CD4(+) T cells, IL-6, and IL-17A, and is enhanced by the pX gene product from human T cell leukemia virus 1 (HTLV-1). Arthritis development in these mice requires that the F759 mutation is present in nonhematopoietic cells, but not in immune cells, highlighting the important role of the interaction between nonimmune tissues and the immune system in this disease. Furthermore, this interaction is mediated by the IL-6 amplifier through STAT3 and NF-kappaB. Ultimately, this model may represent a general etiologic process underlying other autoimmune and inflammatory diseases. More importantly, the understanding of IL-6 has paved the way for new therapeutic approaches for RA and other autoimmune and inflammatory diseases.

[Hermann Lebert (1813-1878): natural scientist, spa doctor, histopathologist and clinician in Switzerland, France and Germany]. / Hermann Lebert (1813-1878): Naturforscher, Badearzt, Histopathologe, Kliniker in der Schweiz, in Frankreich und in Deutschland.

H. Lebert was in many ways an extraordinary personality. He began is career as a scientist performing experimental research in botany and zoology. After a short period as a spa doctor--work he approached on a scientific basis--he performed one of the first microscopic tissue analyses, as well as writing two significant works with a wealth of pictures on pathophysiology and histopathology, thereby paving the way for cellular pathology. In addition to general problems relating to inflammation, he concentrated on tumors and tuberculosis. He was one of the first to recommend pre-operative histology, making him a pioneer of biopsy diagnostics.As a clinician he worked in nearly all areas of internal medicine, including neurology, and published a large number of monographs, of which the first German monograph on acute articular rheumatism was one. Rheumatology played a considerable role in both his histopathological and clinical activities.Of particular interest is the fact that Lebert frequently travelled between Switzerland, France and Germany and was applauded in all three as a great scientist, as awards from both Napoleon III and the Prussian King Friedrich Wilhelm IV can testify.

The classic: total condylar knee replacement in patients who have rheumatoid arthritis. A ten-year follow-up study. 1990.

Eighty knee replacements with a total condylar prosthesis in patients who had rheumatoid arthritis were followed for ten years. At ten years, nineteen knees needed revision and sixty-one prostheses were still functioning. The major reasons for revision were loosening of the tibial component or late bacteremic seeding from another site. Radiolucency at the bone-cement interface adjacent to the tibial component was statistically related to malposition of the tibial component. According to the system of The Hospital for Special Surgery, the mean scores were 64 points preoperatively and 85 points postoperatively. Synovitis recurred in only 3 per cent of the knees. When revision, pain, or radiographic evidence of loosening were considered an indication of failure, the ten-year cumulative survival was 75 per cent.