Artrite Reumatoide. Terapia con Farmaci Biologici
Prof. Gianni Marone
L’ artrite reumatoide (RA) è una malattia autoimmune sistemica con andamento cronico e con carattere di aggressività.
Sebbene la RA sia caratterizzata da infiammazione cronica con interessamento sistemico, la malattia presenta una elettiva localizzazione poliarticolare ed è frequentemente responsabile di grave disabilità.
Ai fini diagnostici occorre la presenza di almeno 4 criteri su 7.
I criteri 1 e 4 devono essere presenti per almeno 6 settimane.
“The relationship between radiological change and the consequences of RA for the patient has not yet been fully established. In particular, the link with long-term disability is assumed rather than proven. One view of this relationship is shown in this slide. The effect of joint destruction comes to dominate disability late in the disease course, while inflammatory joint symptoms are the main determinant of disability early in the disease. Furthermore, the potential consequences for disability of various changes to the rate of radiographic progression may not be immediate. For example, if radiographic progression is halted for four years, it will take perhaps 10 years for the benefit to be clearly appreciated against the background of variation within individual patients. The need for a long-term view makes it difficult to investigate the detailed consequences for disability of a reduction in radiographic change by using randomized, controlled trials of interventions that slow or stop radiographic progression.” Kirwan JR. Conceptual issues in scoring radiographic progression in rheumatoid arthritis. J Rheumatol. 1999;26:720-725
I suddetti paramentri di laboratorio sono non specifici e riflettono sia lo stato di flogosi acuta che cronica, e in talune condizioni possono non essere correlate con la malattia.
Stadi patogenetici
Cytokines involved are: GM-CSF, IFN-γ, IL-1β, IL-6, IL-8, IL-10, IL-12, IL-15, IL-2, IL-17, TGF-β, TNF-α. Early cartilage and bone erosion in rheumatoid arthritis is associated with the accumulation of several cell populations in the synovial membrane and the formation of a proliferating pannus. The synovial sublining layer contains several cell populations including macrophages, T and B lymphocytes, dendritic cells, and polymorphonuclear leukocytes. The lining layer contains large numbers of macrophages and fibroblast like synoviocytes. The interface between pannus and cartilage is occupied pre dominantly by activated macrophage populations and synoviocytes capable of secreting cytokines and destructive proteases in abundance. (Bresnihan B. Pathogenesis of joint damage in rheumatoid arthritis. J Rheumatol. 1999;26:717-719). The greater production of IL-1 by rheumatoid synovium, in comparison with that from patients with osteoarthritis, may be due primarily to the greater numbers of macrophages and higher degree of vascularity of rheumatoid tissue. (Farahat MN, Yanni G, Poston R, Panayi GS. Cytokine expression in synovial membranes of patients with rheumatoid arthritis and osteoarthritis. Ann Rheum Dis. 1993;52:870-875). These results all suggest that IL-1 production is abundant in synovial macrophages, and may be associated with a more active destructive stage of rheumatoid synovitis.
Cytokines present in the joint fluid from patients with rheumatoid arthritis exhibit proinflammatory and anti-inflammatory activities:
“Once in the synovium, activated neutrophils release mediators that stimulate mononuclear leukocytes, synoviocytes, and chondrocytes. These cells release IL-1 (more specifically, IL-1β) and other pro- and anti-inflammatory cytokines. Then, once IL-1 and TNF-α are present, other interleukins (IL-6, IL-8, and IL-10) stimulate local fibroblast proliferation and recruit leukocytes. Although inflamed synovial cells express TNF-α, it is secreted to a far lesser extent than IL-1. Early in the RA disease process, IL-1 causes cartilage degradation by inducing rapid loss of proteoglycans and stimulating the production of neutral proteinases in chondrocytes. Since IL-1 also stimulates osteoclasts, bone resorption occurs”. Van den Berg WB. Joint inflammation and cartilage destruction may occur uncoupled. Springer Semin Immunopathol. 1998;20:149-164
Overlapping Proinflammatory Effects of IL-1 and TNF-α
Although more than a dozen cytokines are believed to be involved in rheumatoid arthritis, IL-1 and TNF-α are thought to play central roles in the pathogenesis of the disease. A listing of the inflammatory effects of IL-1 and TNF-α demonstrates the degree to which their effects are shared. In addition, IL-1 is able to induce the expression of TNF-α, and vice versa, providing further evidence of their functional interrelationship in the pathogenesis of rheumatoid arthritis.
Although overlapping, their effects are not identical. IL-1 has been particularly associated with osteoclast activation and upregulation of angiogenic factors, which may contribute to the bone and cartilage destruction and neovascularization seen in rheumatoid arthritis. TNF-α has been particularly associated with induction of apoptosis, or programmed cell death.
The current treatment options for RA are multifocal. First, nonsteroidal anti-inflammatory drugs are commonly used. In addition, we often use corticosteroids, such as low-dose prednisone, which are often used as bridge therapy or to allow treatment for acute flares. In addition, there are a variety of other more potent, so-called disease-modifying drugs including methotrexate, hydroxychloroquine, sulfasalazine, leflunomide, and others. In the past 5 to 6 years, there have been biologic modifiers, or biologic disease-modifying drugs, approved. Moreover, in the past few years, clinicians have learned that the combination of biologic disease-modifying drugs with some of the synthetic disease-modifying drugs has added benefit and may provide more complete response than either synthetic disease-modifying antirheumatic drugs (DMARDs) or biologic DMARDs when used as monotherapy.
Gli obiettivi principali della terapia dell’AR sono: la riduzione dei sintomi dipendenti dalla infiammazione, quali il dolore, la tumefazione articolare e la rigidità; il miglioramento/ripristino della capacità a svolgere ogni funzione; il ritardare o bloccare l’evoluzione del danno anatomico alle articolazioni. Ciò significa puntare ad un obiettivo ambizioso: la remissione (che significa guarigione di una malattia di cui non si conosce la causa che non può quindi essere eliminata). L’abolizione dell’infiammazione può ripristinare una sopravvivenza paragonabile a quella della popolazione sana.
Potente inibitore competitivo della diidrofolato reduttasi con inibizione dei processi di sintesi del DNA
Impiego terapeutico
Il trattamento con Etanercept è ben tollerato
Reazioni sistemiche all’infusione (infliximab); Reazioni nei siti di iniezione (adalimumab, etanercept); Infezioni (vie aeree superiori, tubercolosi, infezioni opportunistiche); Altre potenziali complicazioni (sindrome Lupus-like, malattie demielinizzanti, tumori); Sviluppo di anticorpi bloccanti
In general, the TNF inhibitors have been shown to be fairly safe in clinical trials. However, some issues have developed at the postmarketing stage that clinicians need to be aware of as they see patients and advise them about these drugs. Infliximab is an agent that is given IV, and infusion reactions have been reported. Although they have been rare, serious, life-threatening anaphylactic reactions may occur. Injection-site reactions, again, are not a serious problem, but they are commonly reported with adalimumab and etanercept; they usually do not result in the need to discontinue the use of the drug. Common infectious complications, such as upper respiratory tract infections, sinus congestion, or infections, have been reported and are easily managed in those patients; however, there have been data published with postmarketing information that opportunistic infections and tuberculosis can be an issue with the TNF inhibitors. It is thus important to carefully screen patients by performing a purified protein derivative (PPD) skin test and chest X-ray prior to starting these drugs to make sure there is no active infection. Less common are drug-induced lupus-like syndrome, demyelinating disorders, and malignancies. These issues continue to be an area of research and need to be resolved with appropriate databases to determine if they are problems that may be part of the RA clinical spectrum or if the TNF inhibitors actually increase the risk of these side effects. Finally, some of these agents may be associated with the appearance of human antichimeric antibodies (HACAs), antibodies that develop against the TNF protein that has been administered. To date, there is very little data published about the clinical significance of these antibodies.
Antagonista ricombinante del recettore dell’IL-1
Anakinra Therapy: Safety
The safety profile with anakinra has been generally positive. Some patients develop injection site reactions. Infectious complications, although not severe, have been reported, including upper respiratory tract infections. More recently, a study published in Arthritis and Rheumatism by Genovese and colleagues has shown that anakinra, when used in combination with etanercept, increases the risk for serious adverse events, and the combination of anakinra with a TNF inhibitor is no longer indicated based on the safety profile as well as data demonstrating that the combination was not more effective in suppressing the disease activity. Although not a major issue, neutropenia has been reported in the clinical trials, especially in combination with the TNF inhibitors. This has been reversible when the TNF inhibitor and the IL-1 blockers were stopped. As with the TNF inhibitors, there is also the potential of developing antibodies to anakinra, but again, these are felt not to be of major clinical significance. Of course, much more work needs to be done in order to understand the true significance and clinical consequences of antibodies to all of the biologic response modifiers.
Anticorpo monoclonale disegnato per depletare selettivamente i B linfociti CD20+
La deplezione dei linfociti B avviene mediante tre possibili meccanismi:
4. Diagnostica strumentale dell'insufficienza cardiaca
7. Ipertensione arteriosa secondaria
8. Epatite
9. Sindrome da immunodeficienza acquisita
10. Asma bronchiale
11. Artrite Reumatoide. Terapia con Farmaci Biologici
12. Patologie Benigne e Disfunzionali dell'Esofago
14. Insufficienza venosa degli arti inferiori
16. Terapia endoluminale delle stenosi esofagee
17. Malattie infiammatorie croniche intestinali
4. Diagnostica strumentale dell'insufficienza cardiaca
7. Ipertensione arteriosa secondaria
8. Epatite
9. Sindrome da immunodeficienza acquisita
10. Asma bronchiale
11. Artrite Reumatoide. Terapia con Farmaci Biologici
12. Patologie Benigne e Disfunzionali dell'Esofago
17. Malattie infiammatorie croniche intestinali
18. La chirurgia laparoscopica
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