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Clin Rheumatol (2010) 29:451–455 DOI 10.1007/s10067-009-1352-3

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Osteoarthritis: can anti-cytokine therapy play a role in treatment? Ana Luisa G. Calich & Diogo S. Domiciano & Ricardo Fuller

Received: 15 June 2009 / Revised: 13 October 2009 / Accepted: 17 December 2009 / Published online: 27 January 2010 # Clinical Rheumatology 2010

Abstract Osteoarthritis (OA) is the most common joint disorder worldwide, and it has an enormous socioeconomic impact both in the United States and throughout the world. The degree of articular inflammation is usually associated with the disease’s progression, indicating that this process could contribute to articular damage. IL-1 beta and antiTNF alpha are the two major cytokines players in the physiopathology of OA. Hence, we aimed to review the current literature on the effects of IL-1 and TNF-alpha neutralization as a new OA therapy. In vitro and experimental models showed a reduction in cartilage destruction with IL-1 inhibition therapy by IL-1 receptor antagonists (IL-1Ra). Despite this favorable evidence in animal models, studies on the inhibition of IL-1R in humans are still scarce. Although there is clear evidence that TNF-alpha plays a role in the pathophysiology of OA, only a few experimental trials have investigated the efficacy of blocking this proinflammatory cytokine in the treatment of OA. So far, the few studies available in humans using anti-TNF-alpha and IL-1 receptor antagonist are not remarkable, suggesting that further investigation and new therapeutic approaches are needed. Keywords IL-1 . Inflammation . Osteoarthritis . TNF-alpha

A. L. G. Calich (*) : D. S. Domiciano : R. Fuller Rheumatology Division, School of Medicine, University of São Paulo, Rua Tabapuã, 1554 ap 1001, 04533-005 São Paulo, Brazil e-mail: [email protected]

Introduction Osteoarthritis (OA) is the most common type of arthritis associated with aging. It dramatically impacts health care because of its effect on ambulation and mobility. It is the leading cause for the several hundred thousand knee and hip replacement surgeries [1, 2]. A subset of these patients develops marked inflammatory disease, and recent evidence from in vitro and in vivo studies indicates that chondrocytes can release and respond to a number of cytokines. Indeed, osteocartilagenous fragments released into the articular cavity are known to trigger chondrocyte inflammatory response [3] with the consequent expression of pro-inflammatory cytokines and proteases such as IL-1 beta and matrix metalloproteinase 13. In addition, histological studies have demonstrated the presence of a pannus-like alteration in OA [4–6] consistent with that observed in rheumatoid arthritis (RA). The transcription level of pro-inflammatory cytokines is, however, lower than that observed in RA [7]. Practical considerations In OA, the degree of articular inflammation is usually associated with the disease’s progression, indicating that this process could contribute to articular damage. Spector et al. showed that CRP levels rise modestly but significantly in woman with early knee OA and that higher levels indicate that the disease will progress over 4 years [8]. Supporting this notion, magnetic resonance image (MRI) studies of knee osteoarthritis revealed an increased thickness of synovial membrane in early OA even in the absence of clinical evidence of inflammation.

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The extent of the thickening of the membranes was consistent with macro and microscopic findings of inflammation [9]. The authors thus suggest that MRI could be used to identify patients who could benefit from a more aggressive anti-inflammatory therapy. The role of cytokines in OA IL-1 beta and anti-TNF alpha are the two major cytokines involved in the physiopathology of OA [10–12]. The former was shown to promote the synthesis of metalloproteases to inhibit the function of growth factors for extracellular matrix proteins, to enhance the expression of cell adhesion molecules, and to stimulate the synthesis of other pro-inflammatory cytokines such as TNF-alpha and IL-6 [10, 13, 14]. TNF-alpha exerts an effect similar to IL-1 and can act synergistically with this cytokine. In this regard, the intra-articular inoculation of IL-1 was compared with IL-1 associated with TNF-alpha and more intense cartilage destruction was detected when both mediators were used simultaneously [12]. Other experimental studies have demonstrated that IL-1 and IL-1 plus TNF-alpha were able to activate inflammatory enzymes in chondrocytes such as nitric oxide synthase (iNOS), cyclooxygenase 2 and phospholipase A2 [15–17]. These findings were confirmed extensively in humans [18–21] with an augmented expression of IL-1 receptors detected in metalloproteinases secreting chondrocytes [18] and by the increased expression of the TNF-alpha receptor p55 observed at sites of focal destruction of cartilage. Interestingly, other pro-inflammatory cytokines such as IL-18 and IL-17 were also associated with catabolic responses of chondrocytes but their role in the etiopathogeny of OA remains to be determined [22, 23]. Anti-IL-1 therapy The possible role of IL-1 inhibition by IL-1 receptor antagonists (IL-1Ra) in reducing the severity of OA was initially demonstrated by in vitro studies [24–26] which showed a reduction of cartilage destruction associated with this therapy (Fig. 1). Animal models of OA have confirmed these findings (Table 1). Local administration of IL-1Ra in dogs reduced macroscopic and microscopic lesions of knee OA. This result was dose-dependent, reinforcing the therapeutic effect of the drug [27]. Interestingly, experimental OA was also inhibited by IL-1Ra gene transfer with a consequent decrease in the severity of cartilage lesions and osteophyte formation [28–30]. Significant macroscopic and microscopic improvements were also observed in the cartilage of animals treated with IL-1Ra genes. The in vivo transcription of the transferred gene in these animal models was confirmed by the increased

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levels of IL-1Ra in the synovial membrane identified by immunohistochemical studies. Moreover, diminished edema, pain, and radiological alterations were also detected in horses [30]. The treatment of OA with diacerein is another evidence of the role of IL-1 inhibition on the pathophysiology of this disease. Diacerein was shown to inhibit the synthesis of IL-1 beta on human OA synovium and reduce the number of chondrocyte IL-1R in vitro [31]. This drug is an effective treatment for symptoms in OA and has a structure-modifying effect when used for a long period [32, 33]. Despite this favorable evidence in vitro and in animal models, studies on the inhibition of IL-1R in humans are still scarce. Intra-articular 150 mg of anakinra, a recombinant form of human IL-1Ra was used to treat 13 patients suffering from knee OA [34] with good drug tolerance. Pain analyzed by the visual analog scale and patients global scores by Western Ontario and McMaster University OA algofunctional index (WOMAC) evaluated on days 2, 3, 4, 11, 30 and 90 of therapy showed a significant reduction. The absence of controls precludes a definitive conclusion on the efficacy of this drug. The same authors performed a double-blinded, placebocontrolled trial with a single intra-articular injection of 150 mg of anakinra and 50 mg of anakinra or placebo in patients with knees OA. A total of 160 patients were randomized to receive the intra-articular injection. The primary end point was the change in the WOMAC score from baseline to week 4. There was no improvement in knee pain, function, stiffness, or cartilage turnover in patients treated with anakinra compared with the placebo. However, the excellent clinical response on day 4 in the 150 mg anakinra group was statistically significant, suggesting that the short half-life of this drug could explain why patients didn’t reach the primary end point. Further studies with longer acting and more potent IL-1 antagonists may better elucidate this potential [35]. Anti-TNF-alpha therapy Despite the clear evidence on the role of TNF-alpha in the pathophysiology of OA, only a few experimental trials have investigated the efficacy of blocking this pro-inflammatory cytokine in the treatment of OA [36, 37]. In humans, a case report described the successful treatment of inflammatory knee OA using adalimumab [36] with remarkable improvement not only in the symptoms but also in MRI findings with an important reduction of synovitis, synovial effusion, and complete resolution of bone marrow edema. The results of the openlabel study with this drug in 12 patients with erosive OA of the hands [37] revealed only a modest improvement in the


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Fig. 1 Sites for the anti-IL-1 and anti-TNF therapy (respectively 1 and 2). a IL-1 and TNF-alpha stimulate cartilage breakdown and synovial inflammation. b IL-1Ra competitively inhibits the binding of IL-1 to IL-1 receptor. c Experimental OA was also inhibited by gene transfer of IL-1Ra. d Anti-TNF can inhibit TNF-alpha and prevent cartilage degradation

number of swollen joints, disability score, pain score, and physician global assessment.

stiffness in patients with knee osteoarthritis [39]. Now, it is undergoing phase III clinical trials for knee and hip pain due to OA [40, 41].

Other therapies While there is no perspective for etiologic treatment of OA with anti-cytokine, a promising biologic for symptomatic relief may be emerging. Tanezumab is a monoclonal antibody against nerve growth factor (NGF). Studies have shown that NGF is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target [38]. In a phase II trial, tanezumab has shown to reduce pain and

Conclusions It is generally accepted that IL-1 and TNF-alpha are the pivotal cytokines involved in OA physiopathology. Hence, the neutralization of these inflammatory mediators appears to be a logical development for OA therapy. So far, the few studies done on humans using anti-TNF-alpha and IL-1

Table 1 Studies on the effects of biological drugs on osteoarthritis Author

In vivo study

Biological therapy/route

Result

Caron et al. [27]

Experimental (dogs)

Recombinant IL-1Ra/IA (intra-articular)

Fernandes et al. [28] Pelletier et al. [29] Frisbie et al. [30]

Experimental (rabbits) Experimental (dogs) Experimental (horses)

IL-1Ra by gene therapy/IA IL-1Ra by gene therapy/IA IL-1Ra by gene therapy/IA

Chevalier et al. [31] Chevalier et al. [32]

Clinical trial Clinical trial

Recombinant IL-1Ra/IA Recombinant IL-1Ra/IA

Grunke et al. [33] Magnano et al. [34]

Case report Clinical trial

Anti-TNF (adalimumab)/subcutaneous Anti-TNF (adalimumab)/subcutaneous

Reduction of: collagenase-1 expression and OA development Reduction of OA progression Reduction of OA progression Reduction of OA progression: histological and clinical improvement. Safety of the drug Improvement in pain (4th day). No benefits at 4th week. Improvement in pain and MRI findings Modest improvement. Primary outcome (ACR20) not met.

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receptor antagonist are not remarkable and suggest that the most promising approach for cytokine targeting in OA may be IL-1Ra gene transfer.


16.

17. Disclosures None

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