Current Medicinal Chemistry (v.22, #16)

Meet Our Editorial Board Member: by Isabel Haro (1889-1889).

Introduction: Tumour necrosis factor (TNF) blocking therapy is an effective treatment for chronic inflammatory arthritis. As circulating TNF might induce or exacerbate the development of congestive heart failure (CHF), several trials have investigated the effect of TNF blocking therapy on CHF. However, due to inefficacy and even a risk of exacerbation of CHF, TNF blocking therapy has since then been contraindicated in patients with advanced CHF, New York Heart Association class III and IV. We review current knowledge on the pathophysiological mechanisms and safety of TNF blocking therapy in chronic inflammatory arthritis patients with regard to CHF. Methods: A systematic search of the literature published up till December 2013 was conducted in MEDLINE, EMBASE and the Cochrane Library to identify all studies investigating the effect of TNF blocking therapy on the occurrence and risk of CHF in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). All articles reporting data on the prevalence or incidence of CHF during treatment with TNF blocking therapy in patients with in RA, AS or PsA were included. Also imaging studies and studies with biomarkers, investigating the effect of TNF blocking therapy on cardiac function were included. Results: In total, 54 studies were included. Results from large prospective registries suggest that first, a potentially harmful effect of TNF blocking therapy on the incidence of CHF in older RA patients cannot be excluded and that no harmful effect was observed of TNF blocking therapy in other patients. Second, we found that TNF blocking therapy potentially improves several echocardiographic parameters of cardiac function in RA, AS and PsA, but due to small sample sizes, these results require validation in larger studies. Third, we found improvement in NT-proBNP levels after use of TNF blocking therapy in both RA and AS. Conclusion: Based on current literature, in patients with chronic inflammatory arthritis and concomitant symptomatic mild-tomoderate CHF (NYHA class I or II), treatment with TNF blocking therapy is not contraindicated. In chronic inflammatory arthritis patients with concomitant symptomatic moderate-to-severe CHF, NYHA class III-IV, treatment with TNF blocking therapy should be avoided if possible. Whenever, treatment with TNF-blocking therapy is considered in these patients consultation with a cardiologist is recommended before treatment is initiated.

Cardiovascular Effects of Methotrexate in Rheumatoid Arthritis Revisited by Tatyana V. Popkova, Diana S. Novikova, Armen Yuri Gasparyan, Evgeny L. Nasonov (1903-1910).
Cardiovascular events such as myocardial infarction (MI) and stroke due to enhanced inflammatory atherosclerosis account for increased premature mortality in rheumatoid arthritis (RA). Accumulated evidence suggests that accelerated atherosclerosis and related cardiovascular comorbidities in RA are confounded not only by traditional risk factors (TRF) but also by a number of immune and inflammatory pathways. Since chronic inflammation and autoimmune disorders play a key role in atherosclerosis and related cardiovascular complications in RA, effective suppression of systemic inflammation can be viewed as a strategy for cardiovascular therapy and prevention in this disease. This article overviews some mechanisms of action of methotrexate on TRF, clinical and subclinical manifestations of RA-induced atherosclerosis, and related cardiovascular morbidity and mortality.

Background: The elevated risk of heart failure (HF) in rheumatoid arthritis (RA) is considered to be partly caused by the chronic low-grade systemic inflammation. As potent suppressors of inflammation, biologics were expected to influence HF development in RA. Unfortunately, case reports of HF in RA patients and non-RA HF studies have suggested that these drugs may even increase HF rates in RA. Aim: With this review we want to provide insight into the molecular mechanisms by which elevated cytokines, immune cell alterations and biologics influence myocardial function in RA patients. Beside preclinical data, clinical studies that assess the influence of biologics on HF development are reviewed. Results: Preclinical studies suggest a bidirectional role of the investigated cytokines (TNF-alpha, IL- 1, IL-6) on myocardial function. Common mechanisms of immune cell alterations in HF and RA have been observed in preclinical studies. High doses of infliximab in non-RA patients with HF were found to be harmful. The vast majority of retrospective studies suggest that TNF-alpha inhibitors do not increase the risk of HF development in RA patients. Nevertheless randomized controlled trials are missing and TNF-alpha inhibitors are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II based on non-RA HF studies. Due to rare adverse events of HF, rituximab is contraindicated in RA patients with HF NYHA IV. Conclusion: Cytokines seem to have a bidirectional influence on HF development in RA. According to the published evidence it is unlikely that TNFalpha inhibitors substantially increase the risk of HF development in an RA population. Nevertheless they are contraindicated in RA patients with HF NYHA III/IV and should be used with caution in RA patients with HF NYHA I/II. The influence of anakinra, tocilizumab, rituximab and abatacept needs to be investigated in future studies.

Biologic agents have expanded the repertoire of efficacious and safe systemic therapies for the treatment of moderate-to-severe psoriasis and active psoriatic arthritis. The biologics act to inhibit key inflammatory molecules that are thought to be involved in the pathogenesis of these chronic inflammatory disorders as well as physiologic immune responses. In this paper, we discuss the proposed molecular mechanisms of action, efficacy, and safety of the two FDA-approved classes of biologics, the tumor necrosis factor inhibitors and the interleukin-12/23 inhibitor. The tumor necrosis factor inhibitors that are reviewed include etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol. The interleukin- 12/23 inhibitor that is discussed is ustekinumab. Specifically, we review the mechanism of action for each biologic agent and the FDA-approved indications and dosing for these therapeutics. We provide up-to-date evidence for the efficacy of these systemic medications using key phase 3 clinical trial data, we highlight important safety information for each biologic based on long-term open-label extension trials and safety registries, and we discuss studies that investigate off-label dosing with the biologics. Each biologic is reviewed in these specific areas of focus for their indicated treatment of psoriasis and/or psoriatic arthritis.

Molecular and Cellular Pathways as Treatment Targets for Biologic Therapies in Systemic Sclerosis by Theodoros Dimitroulas, Dimitrios Daoussis, Alexandros Garyfallos, Petros P. Sfikakis, George D. Kitas (1943-1955).
Recent advances have shed light on the complex pathogenic processes that underlie the development and progression of Systemic Sclerosis (SSc) but management of the disease remains problematic and curative treatment is not available. Better understanding of the underlying pathology has enabled novel therapeutic approaches to be investigated, as therapies in rheumatology are becoming increasingly disease/ organ-specific, targeting unique biological networks and signalling pathways. The pathophysiologic and clinical pleiomorphism of SSc however, represents a major barrier to conducting large well-controlled studies for the evaluation of non-selective immunosuppressive and novel highly selective agents. Therapeutic biologic strategies targeting inflammatory or profibrotic cytokines and lymphocyte activation proved to be efficacious in other systemic rheumatic diseases but have demonstrated contradictory results in SSc. Blocking of tumour necrosis factor alpha and interleukin-6 may improve SSc-associated arthritis, while depletion of B-cells may have benefits for skin and lung fibrosis, but randomized studies are needed. In this review we critically appraise available data for the treatment of SSc focusing on immunologic and antifibrotic strategies. Attenuation of the fibrotic process remains an unmet goal but the potential to prevent damage by promoting tissue repair has been shown in preclinical studies. Translation of these findings into clinical practice will hopefully establish new therapeutic options and improve prognosis of these patients, for which our therapeutic armamentarium remains poor.

Immune Thrombocytopenic Purpura: New Biological Therapy of an Old Disease by Melda Comert Ozkan, Fahri Sahin, Guray Saydam (1956-1962).
Immune Thrombocytopenic Purpura (ITP) is the most common autoimmune disorder that is caused by antibody- mediated destruction of thrombocytes and impaired megakaryocyte platelet production. ITP remains a diagnosis of exclusion. Recent pathophysiologic mechanisms and therapeutical approaches of ITP have emerged. Although steroids and intravenous immunglobulins (IVIg) have still been the main therapeutic strategies, a group of patients develop resistance to those eventually and there have been some biological treatment options such as rituximab especially in the last decade. In this review article, we have summarized the therapeutic options for patients with ITP and mainly focused on the timing and potential effects of biological agents.

Antisynthetase syndrome is a group of closely related rare diseases which clinically manifest with inflammatory myopathies, interstitial lung disease, inflammatory arthritis, skin hyperkeratosis (mechanic's hands) and Raynaud phenomenon. The pathophysiology of antisynthetase syndrome is not entirely understood, but genetic predisposition, viral infections and medication use may play a role. Certain antisynthetase antibodies are associated with various clinical presentations and a lower burden of inflammatory myopathies. Patients with antisynthetase syndrome have a worse prognosis than patients with pure inflammatory myopathies mainly because of interstitial lung disease. Future research should further investigate the pathogenesis of antisynthetase syndrome which could identify new therapeutic targets. It will be also important to study whether patients with AS are at increased risk of cancer and whether certain antisynthetase antibodies have any association with the risk of malignancy.

Currently Used Biologic Agents in the Management of Behcet's Syndrome by Caner Saygin, Didem Uzunaslan, Gulen Hatemi (1976-1985).
Behcet's s yndrome (BS) is a multisystem vasculitis with frequent mucocutaneous, joint, eye and visceral organ involvement. From early 2000s, biologic drugs have been increasingly used in the management of BS, enabling rapid and complete remission in most cases with critical organ involvement. Despite the current experience with steroids and traditional immunosuppressives, biologics are exceptionally promising for treatment of resistant cases. Among the biologics used in BS, TNF-alpha antagonists are the oldest and their efficacy has been proven in recalcitrant ocular, vascular, gastrointestinal and neurologic involvements. These drugs have significantly reduced morbidity and mortality in BS and they have an acceptable safety profile. Tocilizumab, an IL6 receptor antibody, has been shown to be effective in BS patients with neurologic involvement and amyloidosis, and IL1β antagonists such as anakinra, canakinumab, gevokizumab were effective in the management of ocular involvement. Studies investigating the efficacy of daclizumab, IL2 receptor antibody, and secukinumab, IL17 monoclonal antibody, in the management of BS with eye involvement failed to demonstrate significant clinical improvement and both studies were halted. A monoclonal vascular endothelial growth factor antagonist, bevacizumab, was shown to be effective in BS-related macular edema. Alemtuzumab and ustekinumab are among other biologics which were effective in controlling disease symptoms. In this review, we discuss the efficacy and safety of various recently developed biologic agents targeting different pathways involved in the pathogenesis of BS.

Familial Mediterranean fever (FMF) is the most common hereditary autoinflammatory syndrome. FMF is caused by mutations in the MEFV gene which encodes the pyrin protein. FMF is characterized by sporadic, paroxysmal attacks of fever and serosal inflammation, lasting 1-3 days. Patients may develop renal amyloidosis. Colchicine prevents attacks and renal amyloidosis.5% to 10% of the patients with FMF are resistant or intolerant to colchicine. Colchicine resistant patients may receive biological therapies. Anti-interleukin-1 drugs are the most important agents of biological treatments. In this review, colchicine resistance and treatment options will be evaluated.

Thromboangiitis obliterans (TAO) is a thrombotic-occlusive and an inflammatory peripheral arterial disease with unidentified aetiology. Thrombotic events can lead to limb loss in TAO patients, who are typically young male smokers of low socioeconomic status. It is still unknown whether the initial process is thrombosis or inflammation, so it is difficult to ascertain whether managing inflammation or thrombosis improves the outcome of the disease. In this review, the possible mechanisms of thrombosis in TAO are evaluated; the treatments, based on the discussed mechanisms of thrombosis in TAO, are then reviewed and the challenges and limitations associated with the management of TAO are discussed.