Etanercept treatment in rheumatoid arthritis patients with chronic kidney failure on predialysis

Rheumatoid arthritis (RA) patients with chronic kidney failure are intolerant to most disease-modifying antirheumatic drugs (DMARDs) and NSAIDs due to their potential toxicities. Although the tumor necrosis factor (TNF) inhibitors have emerged as a highly effective treatment for RA, their safety and efficacy in RA patients with chronic kidney failure have not been well reported. We retrospectively evaluated the safety and efficacy of etanercept treatment in RA patients with chronic kidney failure. We describe three RA patients with chronic kidney failure who had been treated with DMARDs, steroids and NSAIDs, but were discontinued from these classical agents due to several side effects and nephrotoxicity. The patients were treated with 25 mg of etanercept once or twice a week. We evaluated disease activity and used decreasing renal function and increasing number of infections to monitor safety. All three patients improved after starting etanercept treatment and their steroid requirements were decreased. Linear relationships between Modification of Diet in Renal Disease study equation (MDRD) glomerular filtration rate (GFR) and time were observed. Thus, in all patients, the changes in GFR did not represent superimposed acute drug toxicity, but rather chronic progressive renal failure. These cases show that etanercept may be a safe and effective treatment option for RA patients with chronic kidney failure.     

Recent advances in the treatment of the spondyloarthropathies

PURPOSE OF REVIEW: Recently, there has been renewed interest in the spondyloarthropathy family of chronic inflammatory rheumatic conditions, which has been fueled to a large extent by the biologic era. Over the period of the past 2 years in particular, there have been several notable advances. First, there have been a number of large, high-quality randomized controlled trials evaluating the tumor necrosis factor (TNF) blockers and conservative treatments such as physiotherapy and nonsteroidal anti-inflammatory drugs for use in spondyloarthropathy. This has paved the way for the development of better tools to assess outcome in these patients both in daily practice and in the context of clinical trials. This review uses a systematic approach to outline the most recent (within the last 2 years) and the most pertinent advances in the treatments of the spondyloarthropathies, with particular emphasis on ankylosing spondylitis and psoriatic arthritis. RECENT FINDINGS: Supervised group exercise programs maintain flexibility and posture in patients with ankylosing spondylitis, and spa therapy is a cost-effective treatment option in ankylosing spondylitis. Nonsteroidal anti-inflammatory drugs have a role in symptom modification and, more importantly, may prevent structural disease progression in patients with ankylosing spondylitis when administered continuously at a fixed dose. TNF blockers have been evaluated in a number of randomized controlled trials in ankylosing spondylitis and psoriatic arthritis and have been demonstrated to be safe and effective in the short-term management of these diseases. Longer-term trials are awaited with radiographic outcomes to comment on their disease-modifying properties and their long-term safety and efficacy profiles. SUMMARY: There has been renewed interest in the spondyloarthropathy family of disorders, with an explosion in the number of trials evaluating outcome with the TNF blockers. To date, no cure has been found for the disease, but these agents are emerging as the best therapeutic option available for patients with ankylosing spondylitis and psoriatic arthritis to date.     

Utilidad de los fármacos modificadores de enfermedad (FAME) en el tratamiento de las espondiloartropatías

Disease-modifying antirheumatic drugs (DMARDs), a heterogeneous group of drugs, are widely used in rheumatoid arthritis management. The scientific evidence on the management of spondyloarthropathy with DMARDs is limited and the results are inconclusive. In this article, we review the role of DMARDs in the management of axial involvement in spondyloarthropathies, emphasizing its paradigm, ankylosing spondylitis. We review the data published to date on the efficacy and tolerability of salazopyrin, mesalazine, methotrexate, and leflunomide, as well as those of other drugs used on specific occasions such as pamidronate and thalidomide. Data on the effects of this management on peripheral symptoms and organic disease-like uveitis are also included.     

Association of renal papillary necrosis and ankylosing spondylitis

Three patients with ankylosing spondylitis developed renal papillary necrosis. All had received prosta-glandin synthetase inhibitors including phenylbutazone, indomethacin, or ibuprofen. One patient had sickle trait. These drugs are not commonly associated with papillary necrosis in man, but may adversely effect renal medullary blood flow. An underlying renal vascular abnormality related to ankylosing spondylitis is also considered. Patients with ankylosing spondylitis who are taking prostaglandin synthetase inhibitors should be routinely screened for hematuria.     

Update upon efficacy and safety of etanercept for the treatment of spondyloarthritis and juvenile idiopathic arthritis

TNF-α inhibitors have demonstrated efficacy both as monotherapy and in combination with disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of chronic inflammatory immune-mediated diseases such as rheumatoid arthritis, Crohn’s disease, ulcerative colitis, ankylosing spondylitis (AS), psoriasis (Ps) and/or psoriatic arthritis (PsA) and may be administered off-label to treat disseminated granuloma annulare, systemic lupus erythematosus and systemic sclerosis. There are several TNF-α inhibitors available for clinical use including infliximab, adalimumab, golimumab, certolizumab pegol and etanercept. In this article, we discuss the efficacy and safety of etanercept in the treatment of spondyloarthritis and juvenile idiopathic arthritis (JIA). Etanercept is effective in the treatment of PsA, AS, JIA and uveitis. Independent predictors of achieving a sustained clinical improvement or MDA in children with JIA include shorter disease duration, no concurrent oral corticosteroid use, history of chronic anterior uveitis and age <9 years. IBD incidence was lower in patients receiving etanercept plus MTX. Intra-articular administration of etanercept seems to favor a prompt target joint improvement without serious adverse events. Etanercept improve endothelial function reducing the risk of acute cardiovascular and/or cerebrovascular events. The most commonly reported adverse events were nasopharyngitis, epidermal and dermal conditions, upper respiratory tract infection, cough, headache and fatigue.     

Renal involvement in ankylosing spondylitis: concerning 210 cases

PURPOSE: To define the epidemiology, clinical, biological and histological features of renal diseases in ankylosing spondylitis, ginving special attention to unusual forms. METHODS: We retrospectively reviewed the medical record of 28 cases with renal involvement among 210 cases of ankylosing spondylitis seen over a 27 year period who met the Amor criteria. RESULTS: Twenty-eight of 210 patients (13,3%) presented one or more signs of renal involvement: macroscopic hematuria (4 patients), microscopic hematuria (8 patients), proteinuria (15 patients), nephrotic syndrome (6 patients), decreased renal function (13 patients). Secondary renal amyloidosis and nephrolithiasis (8 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (3 patients). CONCLUSION: The funding of renal abnormalities in 13,3% of our patients suggests that in this illness evidence of renal involvement should be actively investigated in ankylosing spondylitis.     

A 2-year comparative open label randomized study of efficacy and safety of etanercept and infliximab in patients with ankylosing spondylitis

The signs and symptoms of ankylosing spondylitis (AS) respond inadequately to nonsteroidal antiinflammatory drugs, corticosteroids, and disease modifying antirheumatic drugs in quite a number of patients. Tumor necrosis factor inhibitors have demonstrated to be of value in reducing AS disease activity in clinical trials. The efficacy and safety of both etanercept and infliximab in patients with ankylosing spondylitis were compared in a 2-year open label randomised study. Our results are consistent with a significant more rapid clinical improvement in the infliximab treated group. Treatment with both etanercept and infliximab at the end of the study was effective, safe, and well tolerated.     

Spondylarthropathies and anti-TNFalpha drugs

PURPOSE: Spondylarthropathies are a heterogeneous group of disorders including ankylosing spondylitis, psoriatic arthritis, reactive arthritis, arthritis associated with inflammatory bowel disease, and undifferentiated spondylarthropathies. These diseases are characterised by inflammation in the spine, sacroiliac joints, entheses, peripheral joints, and a strong association with HLA-B27; they may cause severe destruction and/or ankylosis in a minority of patients. Conventional treatment includes non steroidal anti-inflammatory drugs, corticosteroid injections, and DMARDs such as sulfasalazine in patients with peripheral arthritis. TNFalpha appears as an important actor in the pathogenesis of spondylarthropathies. METHOD AND RESULTS: Among the anti-TNFalpha drugs, etanercept and infliximab have proved to be effective in the symptomatic treatment of ankylosing spondylitis and psoriatic arthritis. A clinical relapse was observed within a few weeks after treatment discontinuation in a majority of patients. Potential beneficial effects on the destructive and/or ankylosing evolution remains to be confirmed. CONCLUSIONS: Patients with active, severe and refractory spondylarthropathies are potential candidates for treatment with anti-TNFalpha drugs. Taking into account not only the efficacy but also the side effects, with rare but potentially severe complications such as tuberculosis or other opportunistic infections, and the relatively high cost of these drugs, preliminary criteria for the initiation, monitoring and discontinuation of these drugs in the treatment of spondylarthropathies were proposed. Long-term follow-up in large populations of patients with spondylarthropathies is necessary to better define the benefit/risk/cost ratio of anti-TNFalpha drugs.     

Cardiovascular risk in rheumatic patients: the link between inflammation and atherothrombosis

In addition to a high prevalence of the metabolic syndrome and a significant under-diagnosis of vascular risk factors (VRFs), the effect of chronic inflammation also represents the cornerstone of the raised cardiovascular (CV) risk in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Moreover, the finding that among current anti-inflammatory treatments, the use of tumor necrosis factor (TNF)-α blockers is associated with optimal rheumatologic and CV outcomes further supports the impact of inflammation on the CV risk. However, up-to-date treatment guidelines suggest that TNF-α blockers should be used only after the failure of traditional disease-modifying antirheumatic drugs (DMARDs). Early predictors of the therapeutic efficacy of traditional DMARDs are needed to identify candidates for TNF-α blocker treatment. Furthermore, whether the CV risk should be taken into account while choosing antirheumatic treatments is an emerging issue to be addressed. Common educational programs for specialists and general practitioners and appropriate CV prevention programs, taking into consideration traditional VRFs as well as the inflammatory status, should be planned to prevent ischemic events and to achieve optimal inflammation control in rheumatic patients.     

Is retardation of radiologic progression of ankylosing spondylitis possible?

In the introduction is the author dealing with problems of early diagnosis of ankylosing spondylitis and he is explaining the advantages of new ASAS/EULAR criteria for diagnosis of axial spondylarthritis. Than he continues with discussion about new "Recommendations for treatment of ankylosing spondylitis", stressing the modification of recommendations for anti-TNF therapy. Despite the fact, that high symptomatic efficacy of anti-TNF therapy was confirmed, there is no clear evidence that anti-TNF drugs delay radiologic progression. On the contrary, study with nonsteroidal antirheumatic drugs in duration 24 months was performed and have documented that patients treated continuously by celecoxib had smaller radiographic progression than patients treated with celecoxib on demand. Anti-TNF therapy delays radiographic progression in rheumatoid arthritis, but not NSAID, in ankylosing spondylitis it is opposite. The differences may be caused by different pathophysiology of rheumatoid arthritis and ankylosing spondylitis as it is explained in the next part of publication. Combination therapy of AS with anti-TNF and continuous celecoxib therapy could be very interesting.     

Anti-TNFα therapy in ankylosing spondylitis: symptom control and structural damage modification

Anti-TNFα agents represent an outstanding advance in the symptomatic control of patients with ankylosing spondylitis presenting an inadequate response to non-steroidal anti-inflammatory drugs. Anti-TNFα antagonists have demonstrated efficacy and safety in the long-term but continuous therapy is needed for an adequate control of symptoms. After the failure to a first anti-TNFα agent, the use of a second TNFα antagonist seems to be effective and safe. Despite the fast and continuous suppression of bone inflammation, demonstrated by magnetic resonance imaging, the beneficial effect of treatment with TNFα antagonists on the radiological evolution has not been demonstrated to date in ankylosing spondylitis. It seems that insights into new therapeutic molecular targets implicated in the process of ossification are needed.     

强直性脊柱炎相关IgA肾病临床与病理特征

目的：回顾性分析强直性脊柱炎伴IgA肾病的临床病理特点.方法：15例（男12例,女3例）强直性脊柱炎患者,临床有肾脏损害表现,肾活检光镜以系膜增生性病变伴或不伴新月体形成,免疫荧光检查以IgA系膜区沉积为主,回顾分析其临床及病理特征.结果：发生肾损害时强直性脊柱炎病史平均为49.7月（1～240月）,5例患者诊断肾病后才确诊有强直性脊柱炎.13例患者（86.7%）HLA-B27阳性.7例（46.7%）肾损害表现为尿检异常,临床有蛋白尿和镜下血尿;2例（13.3%）以肉眼血尿起病,表现为急性肾炎综合征;6例（40%）起病时表现为慢性肾功能不全.肾活检病理,所有患者均有肾小球系膜和基质增生性病变,8例患者（53.3%）有新月体形成,2例（13.3%）可见节段袢坏死.4例（26.7%）有间质小血管纤维素样坏死,6例（40%）见血管透明变性,3例（20%）间质血管有小血栓形成.10例（66.7%）患者有不同程度的肾小球废弃,4例（26.7%）有半数以上肾小球废弃.8例（53.3%）小管间质中重度纤维化.间质CD68阳性细胞浸润均数为394（188～764）个/mm2.结论：强直性脊柱炎肾脏损害并不少见,临床症状隐匿,容易误诊或漏诊.其肾脏病理改变中突出的血管病变,提示其发病机制不同于原发性IgA肾病,而是继发于强直性脊柱炎.     

Treatment update on spondyloarthropathy

PURPOSE OF REVIEW: The unexpected success of the tumor necrosis factor antagonists in ankylosing spondylitis and psoriatic arthritis has generated considerable enthusiasm regarding the therapeutic potential of these drugs. By contrast, concerns regarding the high cost and long-term safety of the tumor necrosis factor blocking agents have prompted investigators to take a closer look at more traditional anti-inflammatory agents and to explore novel therapeutic targets. The purpose of this review is to summarize treatment advances in spondylarthropathy over the past year and to discuss potential future therapies. RECENT FINDINGS: Recent studies indicate that the morbidity of ankylosing spondylitis and PsA are considerably higher than previously reported. Etanercept, infliximab and adalimumab safely and effectively relieved the signs and symptoms of psoriatic arthritis patients in phase III trials. Etanercept and infliximab were also effective in phase III trials in ankylosing spondylitis. Etanercept slowed radiographic progression in psoriatic arthritis trials, but it is not known whether tumor necrosis factor antagonists can prevent structural damage in ankylosing spondylitis. One trial showed that methotrexate may be effective for relieving the pain of axial disease in ankylosing spondylitis but these findings contradict two previous studies. For reactive arthritis and undifferentiated spondylarthropathy, a combination of antibiotics may be more effective than a single antibiotic for the relief of musculoskeletal symptoms. Last, potential therapeutic targets include interleukin-1, interleukin-12, B lymphocytes, accessory molecules on T lymphocytes, and angiogenic factors. SUMMARY: Phase III trials have confirmed that tumor necrosis factor antagonists are effective and safe for the treatment of ankylosing spondylitis and psoriatic arthritis. For patients who do not respond to tumor necrosis factor blockade, several treatment options are under study. Information from these trials will more clearly define the role of disease-modifying antirheumatic drugs, novel therapeutic agents, and antibiotics in the treatment of spondylarthropathy.     

Update on the treatment of peripheral arthritis in psoriatic arthritis

Psoriatic arthritis is a chronic, disabling disease for which therapies have been borrowed from rheumatoid arthritis and spondylitis. Traditional disease-modifying antirheumatic drugs (DMARDs) remain the first choice for the treatment of peripheral arthritis despite scarce evidence of their efficacy or ability to halt radiographic progression. Tumor necrosis factor antagonists have the greatest level of evidence for symptom control and radiographic progression. They are currently used after the failure of DMARDs to effectively treat peripheral arthritis, enthesitis, and dactylitis, and are the first choice when axial disease predominates. Despite the use of these treatments, 30% to 40% of patients will still have active disease. Among new drugs, evidence of efficacy has already been published with regard to anti-IL12/23 monoclonal antibody (ustekimumab) and golimumab. Results are forthcoming from trials with certolizumab pegol, abatacept, and rituximab. As knowledge of the pathogenesis of psoriatic arthritis evolves and differences among other arthritis conditions become evident, therapies targeting these distinct features are needed.     

New therapeutic approaches for spondyloarthritis

PURPOSE OF REVIEW: Tumor necrosis factor alpha antagonists are effective for signs and symptoms of ankylosing spondylitis. Recent studies have evaluated the efficacy of these agents for structural disease modification. We critically review recent radiographic data suggesting that tumor necrosis factor alpha inhibition may have structure-modifying effects in ankylosing spondylitis, and may thereby alter the disease course. RECENT FINDINGS: Recent studies employing MRI suggest that therapy with tumor necrosis factor alpha antagonists significantly reduces spinal inflammation in active ankylosing spondylitis when compared to placebo; there was no comparable improvement in the severity of chronic stigmata, such as syndesmyophytes and vertebral bridging. These studies were of relatively short duration and small size. SUMMARY: Despite insufficient evidence to conclude definitively that tumor necrosis factor alpha-antagonist therapy provides durable and effective structure modification in ankylosing spondylitis, the data strongly suggest a benefit, at least in the short term. In the future, MRI data coupled with clinical outcomes in larger cohorts followed for longer durations may result in a paradigm shift for ankylosing spondylitis treatment similar to that undergone for rheumatoid arthritis, where patients with ankylosing spondylitis are offered therapy early in the disease course to arrest and prevent structural disease progression.     

Therapie der Psoriasisarthritis

In psoriatic arthritis (PsA) the heterogeneous spectrum of the disease with arthritis/synovitis, axial manifestation, enthesitis, dactylitis, psoriatic skin disease and nail psoriasis has to be considered. Moreover, PsA activity and severity as well as comorbidities are of importance for making therapeutic decisions. Measurement instruments developed for therapeutic studies of rheumatoid arthritis or ankylosing spondylitis are often not appropriate for application in PsA investigations. In this paper established therapies with nonsteroidal antirheumatic drugs, disease modifying antirheumatic drugs (DMARDs) and TNF-alpha inhibitors and the current EULAR guidelines from 2012 are reviewed. However, there is a need for new therapeutic agents for those patients who do not respond to or do not tolerate the current therapies. Other biologic agents have also been tested for PsA with moderate effects only. New therapeutic options could result from the anti-IL12 and anti-IL23 receptor monoclonal antibody ustekinumab and from small molecules such as the oral PDE-4 inhibitor apremilast.     

Was ist gesichert in der Therapie der axialen Spondyloarthritis?

The new term axial spondyloarthritis (axSpA) includes classic ankylosing spondylitis and non-radiographic (nr-) axSpA. The definition was introduced in 2009 as part of the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for axSpA, where—apart from chronic back pain starting before the age of 45 years and the presence of HLA-B27—magnetic resonance imaging demonstrated bone marrow edema of the sacroiliac joints (osteomyelitis) or structural changes on x-rays may play an important role. These criteria can also be used for diagnosis. A major advantage of the new criteria is the identification of patients in early disease stages. In addition to physical therapy, drug treatment with steroidal anti-inflammatory agents (NSAIDs), corticosteroid injections, and biologics [blocker of tumor necrosis factor (TNF)] have all been shown to be effective, while conventional disease modifying drugs (DMARDs) such as sulfasalazine and methotrexate seem to work mainly for peripheral arthritis but not for enthesitis. Biologics are indicated when NSAIDs in optimal dosage have failed. Both these drugs have the potential to improve pain, stiffness, and function but they may also have an influence on new bone formation (syndesmophytes). NSAIDs need to be given continuously and biologics for longer periods of time. Patients with elevated C-reactive protein levels benefit most when treated consequently.     

Renal toxicity associated with disease-modifying antirheumatic drugs used for the treatment of rheumatoid arthritis

OBJECTIVE: To provide a review of the renal toxicity of disease-modifying antirheumatic drugs (DMARDs) currently used for the treatment of rheumatoid arthritis. METHODS: Papers in American and European medical journals related to renal toxicity of DMARDs used for the treatment of rheumatoid arthritis were reviewed. Specific DMARDs reviewed were cyclosporine, gold, D-penicillamine, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, infliximab, and DMARD combination therapy. RESULTS: The renal toxicity of DMARDs varies widely. Cyclosporine, gold, and D-penicillamine all have a serious potential for renal side effects, particularly in the elderly or in patients with compromised renal function. Concomitant use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the potential for renal damage. In contrast, methotrexate, azathioprine, antimalarials, sulfasalazine, leflunomide, etanercept, and infliximab have relatively little renal toxicity. CONCLUSIONS: The potential for renal toxicity should always be considered when determining which DMARD to use for RA therapy. DMARDs that combine efficacy with negligible renal adverse effects should be used for the treatment of patients susceptible to DMARD-associated renal damage.