Leflunomide: efficacy and safety in clinical trials for the treatment of rheumatoid arthritis

Leflunomide is a new disease modifying antirheumatic drug (DMARD) that inhibits lymphocyte proliferation by blocking dihydroorotate dehydrogenase (DHODH), the enzyme critical for the production of pyrimidine necessary for DNA synthesis. Through this mode of action, leflunomide inhibits the lymphocyte proliferation associated with the clonal expansion of T cells in rheumatoid arthritis (RA). In clinical trials, leflunomide was superior to placebo and comparable to sulfasalazine and methotrexate for improving both the signs and symptoms of RA. Leflunomide was also superior to placebo and sulfasalazine and comparable to methotrexate in overall improvement of physical function. Leflunomide was equivalent to methotrexate and sulfasalazine in retarding disease progression measured radiographically. Due to its unique mode of action in the treatment of RA, leflunomide shows value in combination therapy with methotrexate for patients refractory to methotrexate alone. The most common adverse reactions associated with leflunomide therapy include gastrointestinal symptoms, allergic reactions, reversible alopecia and elevated liver enzymes. Adverse events were generally mild to moderate, and resolved without complication. The results of phase II and phase III clinical trials indicate that leflunomide is a safe and efficacious drug for the treatment of RA.     

Leflunomide: a review of its use in active rheumatoid arthritis

A77 1726, the active metabolite of leflunomide, is an immunomodulator which inhibits cell proliferation in activated lymphocytes in patients with active rheumatoid arthritis. Because A77 1726 has a long half-life (approximately 2 weeks), treatment with oral leflunomide is initiated with a loading dose of 100mg once daily for 3 days and continued with 20mg once daily. Results of large randomised, double-blind, multicentre trials of up to 24 months' duration have shown that leflunomide is significantly superior to placebo and at least as effective as sulfasalazine in improving primary outcome measures, such as tender joint counts, swollen joint counts and physicians' and patients' global assessment, in adult patients with active rheumatoid arthritis. Whereas improvement in all primary outcome measures with leflunomide was similar to or significantly less than that with methotrexate after 12 months, the efficacy of both agents was similar after 24 months. The therapeutic effect of leflunomide appears earlier (at 4 weeks) than that of sulfasalazine or methotrexate, and reduction from baseline values in functional disability was significantly greater with leflunomide than with sulfasalazine, methotrexate or placebo at end-point. Leflunomide was at least as effective as sulfasalazine or methotrexate in delaying the rate of radiological progression of disease. The most common adverse events reported in patients receiving leflunomide in randomised double-blind, placebo-controlled trials were diarrhoea (27%), respiratory infections (21%), nausea (13%), headache (13%), rash (12%), increased serum hepatic aminotransferases (10%), dyspepsia (10%) and alopecia (9%). Leflunomide was as well tolerated as sulfasalazine or methotrexate in clinical trials. Monitoring of serum hepatic enzyme levels is recommended in patients receiving leflunomide. The drug is not recommended in female patients who are or may become pregnant. Drug treatment should be discontinued, and hastened drug elimination procedure should be considered, in male patients wishing to father a child. 16 potential cases of pancytopenia and 9 cases of serious skin reactions have been associated with the use of leflunomide in 76,000 patients to date. CONCLUSIONS: Leflunomide is a disease-modifying antirheumatic drug which reduces the signs and symptoms of inflammatory arthritis and delays the radiological progression of disease in adult patients with active rheumatoid arthritis. The drug appears to be as effective and as well tolerated as sulfasalazine or methotrexate, and represents a suitable alternative to these agents in adult patients with active rheumatoid arthritis. Benefits with leflunomide are evident within 4 weeks and efficacy is maintained for durations of up to 24 months.     

Leflunomide for rheumatoid arthritis

Disease-modifying antirheumatic drugs (DMARDs) are given to patients with rheumatoid arthritis (RA) to prevent synovitis, slow destruction of articular cartilage and bone, preserve function and control systemic manifestations of the disease. Recognition that irreversible joint damage often occurs early in RA has led to much prompter use of DMARDs, with sulfasalazine or methotrexate commonly considered the treatment of first choice. Leflunomide (Arava-Aventis) is a new DMARD, licensed for the treatment of adults with active RA. The manufacturer claims that leflunomide has "comparable efficacy to methotrexate and sulphasalazine", with a "faster onset of action", and an "acceptable tolerability profile". Here, we consider the place of leflunomide in the management of patients with RA.     

Leflunomide: new indication. In psoriatic rheumatism: too many risks, too little efficacy

(1) The severity of joint involvement in psoriatic rheumatism varies greatly and its outcome is difficult to predict; some patients have long-term spontaneous remissions. The best-evaluated slow-acting treatments are sulfasalazine and methotrexate; adding etanercept can help some patients who do not respond to these drugs. (2) Leflunomide, an immunosuppressant drug, is already marketed for the treatment of rheumatoid arthritis, a condition for which it shows a less favourable risk-benefit balance than methotrexate. (3) Leflunomide is now licensed in France for "active psoriatic rheumatism". (4) The only available clinical data come from a double-blind placebo-controlled trial in 190 patients. On the basis of a combined outcome measure, significantly more patients responded to leflunomide than to placebo (59% versus 29.7%). However, the patients' global assessment was less positive: 15.8% of patients felt their condition had deteriorated during leflunomide therapy, compared to 24.2% of patients in the placebo group. The study population was too heterogeneous to show which types of patients might benefit most from leflunomide therapy. (5) Pharmacovigilance studies have confirmed some severe adverse effects (hepatic, cutaneous and haematological) and have uncovered other previously unrecognised effects such as interstitial pneumonia, hypertension, weight loss, and peripheral neuropathies. (6) In France, leflunomide treatment costs nearly 10 times more than methotrexate. (7) We conclude that leflunomide should not be used to treat psoriatic rheumatism.     

Leflunomide: a novel DMARD for the treatment of rheumatoid arthritis

Leflunomide (Arava(trade mark), Hoescht Marion Roussel, now Aventis Pharma) is a new, oral disease modifying antirheumatic drug (DMARD) for the treatment of active rheumatoid arthritis (RA). It is a novel isoxazole derivative, which has shown both anti-inflammatory and immunomodulatory properties. Leflunomide primarily acts by inhibiting the de novo synthesis of pyrimidine nucleotides (and consequently DNA and RNA) in immune response cells, particularly activated T-cells. It also inhibits tyrosine kinases, with a subsequent reduction in the pro-inflammatory cytokines, TNF and IL-1. Leflunomide is significantly more effective than placebo and equivalent to sulfasalazine and methotrexate in short-term (26 - 52 week) studies, as measured by American College of Rheumatology (ACR) criteria. It has shown significant improvements in functional disability and health related quality of life and has consistently been shown to slow radiographic progression of RA. Leflunomide has a rapid onset of action (within 4 weeks) which is significantly faster than placebo and sulfasalazine. Leflunomide was well-tolerated in clinical trials with no serious adverse effects occurring. The most common side effects were gastrointestinal disturbances, reversible alopecia, rash, hypertension and abnormal liver function tests. Most of these were mild to moderate and resolved without any complications. In summary leflunomide is an effective and well-tolerated DMARD that is a welcome addition to the currently available DMARDs for the treatment of this disabling condition.     

Safety and efficacy of disease-modifying anti-rheumatic agents: focus on the benefits and risks of etanercept.

The traditional approach to the treatment of rheumatoid arthritis (RA) has been the use of nonsteroidal anti-inflammatory drugs usually in combination with a disease-modifying antirheumatic drug (DMARD) such as hydroxychloroquine, gold, sulfasalazine, methotrexate, leflunomide or cyclosporin. Each of these DMARDs has its own distinct toxicities but has also been shown to be effective in reducing signs and symptoms of disease and to some extent, reduce radiological progression. Within the past 10 years, the combination of several traditional DMARDs has been shown to have increased efficacy over monotherapy without a significant increase in toxicity in a majority of studies. Recently, the US Food and Drug Administration has approved infliximab, a chimeric monoclonal antibody to tumour necrosis factor (TNF)-alpha in combination with methotrexate, for the treatment of signs and symptoms of RA, delay of radiological progression of disease and improvement of physical function while anakinra, an interleukin-1 receptor antagonist, has been approved for the treatment of the signs and symptoms of RA either as monotherapy or in combination with methotrexate. Etanercept is the first biological response modifier approved for use in RA in the US. Double-blind, randomised controlled studies have shown etanercept to be effective therapy in patients with RA who have had inadequate response to DMARDs, in combination with methotrexate, and as early monotherapy. Similar results were seen in juvenile and psoriatic arthritis in DMARD nonresponders. Open-label studies have shown efficacy in adult Still's disease, ankylosing spondylitis, progressive systemic sclerosis, Wegener's granulomatosis and chronic uveitis. Safety issues are a concern because of the ubiquitous role of TNF. To date the only consistent adverse event seen with etanercept has been injection site reactions. Infections occur at the same rate and with the same frequency as the placebo population. There should be caution, however, with using etanercept in patients with a serious infection, or recurrent infections or patients with untreated or latent tuberculosis. As of yet there has not been seen an increase of malignancies. Rare neurological and haematological events have been noted. Etanercept has been a significant addition to the armamentarium of medications for the treatment of RA, juvenile and psoriatic arthritis. Preliminary data show that it may be well tolerated and effective in other rheumatic diseases in which there is over production of TNFalpha.     

Pharmacological treatment of ankylosing spondylitis: a systematic review

The purpose of this study was to review the evidence regarding the efficacy and safety of pharmacological therapies currently available for the treatment of ankylosing spondylitis (AS).A literature search using MEDLINE from 1966 through to April 2005 and a hand search of abstracts from the American College of Rheumatology (ACR) meetings for 2001 through to 2004 were performed. References of articles retrieved were also searched.The MEDLINE search yielded 570 citations and 157 abstracts from ACR were identified. Eighty-four studies were randomised controlled trials (RCTs); 53 fulfilled the inclusion criteria (pharmacological treatment of AS and RCT) and were included in this review. Statistical pooling of data was not performed because of the disparate outcome measures used. Eight RCTs found nonselective NSAIDs and two RCTs found cyclo-oxygenase (COX)-2-selective NSAIDs to be superior to placebo for relief of pain and improvement in physical function. Twenty-nine RCTs showed comparable efficacy and safety between nonselective NSAIDs. One RCT showed no difference between methylprednisolone 1g and 375 mg. Seven RCTs assessing the efficacy of sulfasalazine (sulphasalazine) and two RCTs of methotrexate provided contradictory evidence as to their benefit for treatment of AS. One RCT showed intravenous pamidronate 60 mg to be more effective than 10mg intravenously for the treatment of axial pain. All six RCTs of anti-tumour necrosis factor (TNF)-alpha agents demonstrated superiority to placebo for the treatment of axial and peripheral symptoms.Nonselective as well as COX-2-selective NSAIDs can be used for pain control in patients with AS. Other proven treatment options include sulfasalazine for the treatment of peripheral joint symptoms, while limited evidence supports the use of pamidronate or methotrexate, which require further studies. Anti-TNFalpha agents have been found very effective for the treatment of both peripheral and axial symptoms in patients with AS, but their use is limited by cost and uncertainty over long-term efficacy and safety.     

Systematic review: short-term adverse effects of 5-aminosalicylic acid agents in the treatment of ulcerative colitis

AIM: To determine whether there is a difference in short-term adverse events in patients with ulcerative colitis treated with mesalazine, olsalazine or balsalazide. METHODS: MEDLINE was searched for articles published until 2002. Randomized trials of oral mesalazine, olsalazine or balsalazide for the treatment of active disease or the maintenance of remission were included. Outcomes of interest were the frequencies of patients experiencing adverse events and those withdrawn due to adverse events. RESULTS: Forty-six trials were included. One study of mesalazine vs. sulfasalazine for active colitis showed significantly fewer patients with adverse events with mesalazine. Both balsalazide vs. sulfasalazine studies for active disease showed significantly fewer withdrawals with balsalazide. One trial of balsalazide vs. sulfasalazine for maintenance showed significantly fewer patients with adverse events with balsalazide. Otherwise, no significant differences in safety outcomes were noted. CONCLUSION: All three 5-aminosalicylic acid agents are safe in the short term. In mesalazine-treated patients, the frequencies of adverse events or withdrawals due to adverse events were comparable with those in placebo-treated patients and lower than those in sulfasalazine-treated patients. Overall, adverse events or withdrawals were not significantly more frequent with olsalazine than with placebo or sulfasalazine. Adverse events and study withdrawals on balsalazide were less frequent than those on sulfasalazine.     

Leflunomide: long-term clinical experience and new uses

Leflunomide (Arava, Aventis Pharmaceuticals) is an oral pyrimidine synthesis inhibitor with immunomodulatory and anti-inflammatory activity. This agent has demonstrated significant efficacy in the treatment of rheumatoid arthritis (RA) and psoriatic arthritis in randomised, double-blind, placebo-controlled trials. Both the efficacy and safety of leflunomide are maintained with long-term administration in patients with RA. Leflunomide compares favourably with other biological and non-biological agents used to treat RA in the incidence of adverse events and serious adverse events. Economic studies indicate that leflunomide is a cost-effective option in the treatment of RA. New investigations with leflunomide have focused mainly on combination regimens for the treatment of RA and the use of leflunomide in other inflammatory or autoimmune disorders.     

Economic comparison of leflunomide and methotrexate in patients with rheumatoid arthritis: an evaluation based on a 1-year randomised controlled trial

OBJECTIVE: To compare disease-related medical care and productivity costs, and utilities, in 482 patients with rheumatoid arthritis randomised to receive leflunomide, methotrexate or placebo during a 12-month period. DESIGN AND SETTING: Prospective pharmacoeconomic analysis of a 1-year randomised double-blind trial set in North America. PERSPECTIVE: Societal and the Ontario Ministry of Health. METHODS: Information on healthcare resources, out-of-pocket expenses, loss of working time and time spent on chores, related to the disease or the medication, were collected at 4-week intervals and at study discontinuation. Rating scale and standard gamble (SG) utilities (0 = worse; 100 = best) were collected at baseline and at 6 and 12 months or study exit. Medical care costs in Canadian dollars (Can dollars) were calculated using Ontario reimbursement schedules. US patients' expenses were converted to Can dollars using 1995 purchasing power parity. Lost wages were calculated by age and gender according to 1995 Canadian wage data. All costs were adjusted to 1999 Can dollars and arithmetic mean costs were compared using the nonparametric bootstrap. Analysis of covariance was performed to compare utilities between groups. RESULTS: Mean (standard deviation) rating scale values and SG utilities, respectively, for leflunomide, methotrexate and placebo were 67.7 (18.0), 64.8 (18.1) and 57.5 (9.2), and 80.2 (22.1), 83.2 (18.0) and 77.0 (20.5). Both leflunomide and methotrexate had higher rating scale values (p < 0.05) compared with placebo; SG utilities were significantly different between methotrexate and placebo (p < 0.05). Annualised total rheumatoid arthritisb- or drug-related costs for leflunomide, methotrexate and placebo, respectively, were Can dollars 1761, Can dollars 1280 and Can dollars 1324, and medical care costs were Can dollars 753, Can dollars 620 and Can dollars 167 (all costs exclude drug acquisition and monitoring costs). Annual drug acquisition/ routine monitoring costs were estimated, respectively, at Can dollars 3853/Can dollars 483 for leflunomide and Can dollars 258/Can dollars 599 for methotrexate. Differences between overall costs (excluding drug acquisition and monitoring costs) and medical care costs were not statistically significant. The costs of treating patients with leflunomide were significantly higher than for methotrexate when drug acquisition and monitoring costs were included (p < 0.0001). CONCLUSIONS: No statistically significant differences in utilities could be found between leflunomide or methotrexate. When drug monitoring and acquisition costs are excluded, leflunomide has an otherwise similar economic profile compared with methotrexate, the current gold standard. The acquisition cost of leflunomide is a driving factor in increasing the costs of therapy. These higher costs need to be assessed relative to the therapeutic value of leflunomide.     

来氟米特治疗类风湿关节炎研究进展

来氟米特是第一个专门针对类风湿关节炎的改善病程药,具有独特的作用机制,国内外临床试验发现,来氟米特对类风湿关节炎有很好的治疗效果。可以有效地控制疾病的进展,阻止骨质破坏,改善患者的生活质量,不良反应少,程度轻,具有较好的应用前景。     

Cost-effectiveness of TNF-alpha-blocking agents in the treatment of rheumatoid arthritis

The current literature covering cost-effectiveness and cost-utility analyses of biological treatments in patients with rheumatoid arthritis (RA) are reviewed in order to discuss options and limitations for future application of these highly priced drugs in routine clinical practice. The cost-effectiveness and cost-utility ratios of the studies analysed are converted into the corresponding Euros of the publication year. Etanercept treatment achieved a cost-effectiveness ratio of 44,300 Euros (2002)/ACR 20 (20% response according to American College of Rheumatology criteria) and 43,100 Euros (2002)/ACR 70WR (ACR 70 weighted response) compared with sulfasalazine and methotrexate, respectively, in methotrexate-naive RA. In methotrexate-resistant RA, the combination of etanercept and methotrexate is compared to a combination therapy of methotrexate, sulfasalazine and hydroxychloroquine revealing costs of 46,100 Euros (2000)/ACR 20, and 37,700 Euros/ACR 70WR. The cost-utility ratios for infliximab treatment range from 16,000 Euros to almost 166,000/QALY (quality adjusted life-year) gained, the studies investigating etanercept treatment show a ratio of approximately 25,000 Euros and 120,000/QALY gained. No substantial differences of cost-utilities of infliximab and etanercept were found. The administration of these drugs as third-line therapy is regarded cost-effective compared to other well-accepted therapies with comparable cost-utility ratios of < 50,000 Euros/QALY gained. Still, data on economic outcomes of RA trials are sparse and further cost-effectiveness and cost-utility evaluations are needed.     

Cost-effectiveness of TNF-α-blocking agents in the treatment of rheumatoid arthritis

The current literature covering cost-effectiveness and cost-utility analyses of biological treatments in patients with rheumatoid arthritis (RA) are reviewed in order to discuss options and limitations for future application of these highly priced drugs in routine clinical practice. The cost-effectiveness and cost-utility ratios of the studies analysed are converted into the corresponding Euros of the publication year. Etanercept treatment achieved a cost-effectiveness ratio of €44,300 (2002)/ACR 20 (20% response according to American College of Rheumatology criteria) and €43,100 (2002)/ACR 70WR (ACR 70 weighted response) compared with sulfasalazine and methotrexate, respectively, in methotrexate-naive RA. In methotrexate-resistant RA, the combination of etanercept and methotrexate is compared to a combination therapy of methotrexate, sulfasalazine and hydroxychloroquine revealing costs of €46,100 (2000)/ACR 20, and €37,700/ACR 70WR. The cost-utility ratios for infliximab treatment range from €16,000 to almost 166,000/QALY (quality adjusted life-year) gained, the studies investigating etanercept treatment show a ratio of ～ €25,000 and 120,000/QALY gained. No substantial differences of cost-utilities of infliximab and etanercept were found. The administration of these drugs as third-line therapy is regarded cost-effective compared to other well-accepted therapies with comparable cost-utility ratios of < €50,000/QALY gained. Still, data on economic outcomes of RA trials are sparse and further cost-effectiveness and cost-utility evaluations are needed.     

Methotrexate intolerance in elderly patients with rheumatoid arthritis: what are the alternatives?

Rheumatoid arthritis (RA) in the elderly may be mild or severe, with features that are similar to those seen in younger patients. As such, the treatment regimen in the elderly is almost the same as in younger patients. Methotrexate is the most popular disease-modifying antirheumatic drug (DMARD) for the treatment of RA in the US and Europe. It has excellent efficacy and an acceptable toxicity profile. However, a number of patients do not tolerate methotrexate and an alternative DMARD should be chosen.In the elderly, choice of an alternative DMARD should be made after careful consideration of several age-related factors including concomitant diseases, existing medication, drug compliance, and altered age-related physiology and pharmacokinetics.In elderly patients with RA who are unable to tolerate methotrexate, the alternatives are hydroxychloroquine or sulfasalazine for mild-to-moderate disease and cyclosporin or leflunomide for severe disease, given in combination with low-dose oral corticosteroids. This is primarily due to their efficacy combined with a relatively low toxicity profile compared with other DMARDs, such as gold compounds, penicillamine, azathioprine and alkylating agents. Where the above DMARDs are contraindicated, anticytokine therapy should be considered.The therapy of RA is a dynamic process and requires a delicate balance of benefits and risks. Experience and familiarity with the currently available agents, and knowledge of the nature of the disease are necessary in order to make better therapeutic decisions.     

Treatment of rheumatoid arthritis.

PURPOSE: Current and investigational treatments of rheumatoid arthritis (RA) are described. SUMMARY: The current therapies used to treat RA include nonsteroidal antiinflammatory drugs (NSAIDs), used for the management of pain and inflammation; disease-modifying antirheumatic drugs (DMARDs), used as first-line therapy for all newly diagnosed cases of RA; and biological-response modifiers, targeted agents that selectively inhibit specific molecules of the immune system. Glucocorticoids and other antirheumatic drugs are also used to treat RA. DMARDs include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. NSAIDs and glucocorticoids are effective in controlling the pain, inflammation, and stiffness related to RA. Unlike NSAIDs, they slow clinical and radiographic progression of RA. The biological-response modifiers include infliximab, etanercept, and adalimumab (inhibitors of tumor necrosis factor [TNF]-alpha); anakinra, a recombinant inhibitor of interleukin-1; abatacept, the first costimulation blocker; and rituximab, a chimeric anti-CD20 monoclonal antibody. Investigational therapies for RA include anti-interleukin-6-receptor monoclonal antibodies, new TNF-alpha inhibitors (including one for oral administration), and antibodies against proteins critical for B-cell function and survival. Data accumulated in the past decade favor early aggressive therapy for patients suspected of having RA, including early referral to a rheumatologist, new diagnostic techniques, and aggressive therapy with DMARDs, glucocorticoids, and biological agents. The benefits of this approach have been demonstrated in clinical trials. CONCLUSION: Pharmacologic treatments of RA include NSAIDs, glucocorticoids, DMARDs, and biological agents. With an improved understanding of the pathophysiology of RA and the evidence from various clinical trials with the agents, early aggressive therapy with a combination of drugs or biological agents may be warranted for the effective treatment of RA.     

Quetiapine for acute mania in bipolar disorder.

PURPOSE: The efficacy and tolerability of quetiapine in the treatment of acute mania were reviewed. SUMMARY: Five randomized, placebo-controlled trials involving quetiapine as monotherapy or adjunct therapy in combination with either divalproex or lithium in the treatment of bipolar mania in either adolescents or adults were identified and reviewed. The primary outcome measure used in the trials was a change in Young Mania Rating Scale total scores. Monotherapy trials evaluated quetiapine, lithium, haloperidol, and placebo. Quetiapine was superior to placebo in both trials. Quetiapine and lithium showed comparable efficacy in one study, though lithium serum concentrations may have been suboptimal. Haloperidol was superior to quetiapine in efficacy at day 21 but similar at day 84. In the two trials evaluating quetiapine or placebo as adjunct therapy to lithium or divalproex, quetiapine was significantly more efficacious than placebo in one trial. In adolescents, quetiapine was more effective than placebo as an adjunct to divalproex. The most common adverse effects clearly attributable to quetiapine in these trials were somnolence and dry mouth. Quetiapine did not induce extrapyramidal effects, but weight gain was notable with the drug. CONCLUSION: While quetiapine treatment demonstrated efficacy in the majority of the studies, the robustness of its efficacy is questionable. The use of quetiapine as first-line therapy for acute mania is not recommended based on the available results and cost considerations. However, it may be a useful second-line agent, particularly when sensitivity to extrapyramidal symptoms limits treatment options.     

Role of spleen tyrosine kinase inhibitors in the management of rheumatoid arthritis

Spleen tyrosine kinase (Syk) is a cytoplasmic tyrosine kinase involved in signalling in many of the cells that drive immune inflammation. The development of small molecules that inhibit Syk kinase may change the way we treat disorders such as rheumatoid arthritis (RA), as well as a range of other inflammatory diseases. Fostamatinib (R-788) is an orally bioavailable small molecule. It is the prodrug of R406, which is a potent Syk inhibitor. Fostamatinib was developed because it has more favourable physiochemical properties. It is rapidly converted to R406 by intestinal enterocytes. It has been evaluated in experimental models of RA, such as collagen-induced arthritis. In these models, fostamatinib suppressed clinical arthritis, bone erosions, pannus formation and synovitis. A phase II programme with fostamatinib has largely been completed. Three key trials have been published, lasting 12-26 weeks and each enrolling 189-457 patients (875 in total). All these trials involved placebo therapy and patients continued to receive methotrexate in addition to active treatment with fostamatinib. The first dose-ranging trial evaluated three treatment doses in RA patients who had not fully responded to methotrexate therapy. The second trial compared two treatment doses in patients who had not responded to methotrexate therapy. The third trial compared a single treatment dose with placebo in patients who had not responded to biological therapy. The primary outcome measure was the number of patients achieving American College of Rheumatology (ACR) 20% (ACR20) responses. Placebo ACR20 response rates in all three trials were similar (35-38%). All three trials involved one treatment arm receiving fostamatinib 100 mg twice daily; ACR20 responses with this active treatment ranged from 38% to 67%. A meta-analysis of ACR responses in these trials, using responses to the highest dose in each trial for comparisons with placebo therapy in a random effects model, showed a borderline benefit with ACR20 responses. There were more significant differences with ACR50 and ACR70 responses. The reason that this meta-analysis was not more strongly positive is that the third trial, which evaluated patients who had failed to respond to biological treatments, gave negative results. Individual ACR response components, such as changes in swollen joint counts, showed significant differences in the first two trials, but there were no definite treatment benefits in the third trial. Overall, the differences were significant in a meta-analysis of all three trials. The most important adverse reactions were diarrhoea, neutropenia and raised ALT levels, which all showed significant excesses with active treatment compared with placebo. Too few patients have been studied for a definitive safety profile to be known. Overall, the results of the phase II trials were sufficiently encouraging for a phase III programme to be initiated. It will be some years before their definitive results are available.     

Human dihydroorotate dehydrogenase inhibitors, a novel approach for the treatment of autoimmune and inflammatory diseases

Dihydroorotate dehydrogenase (DHODH), a novel and recently discovered enzyme, is involved in the biosynthesis of uridine. Leflunomide (CAS 75706-12-6), a drug approved for the treatment of treat rheumatoid arthritis (RA), was identified as an inhibitor of DHODH. Structure based drug design using the leflunomide/DHODH X-ray structure yielded novel inhibitors with improved pharmacological properties. Such drug candidates are in clinical trials against various autoimmune diseases.     

Upadacitinib in Rheumatoid Arthritis: A Benefit–Risk Assessment Across a Phase III Program

Treating to a target of clinical remission or low disease activity is an important principle for managing rheumatoid arthritis (RA). Despite the availability of biologic disease-modifying antirheumatic drugs (bDMARDs), a substantial proportion of patients with RA do not achieve these treatment targets. Upadacitinib is a once-daily, oral Janus kinase (JAK) inhibitor with increased selectivity for JAK1 over JAK2, JAK3, and tyrosine kinase 2. The SELECT phase III upadacitinib clinical program comprised five pivotal trials of approximately 4400 patients with RA, including inadequate responders (IR) to conventional synthetic (cs)DMARDs or bDMARDs. This review aims to provide insights into the benefit–risk profile of upadacitinib in patients with RA. Upadacitinib 15 mg once daily, in combination with csDMARDs or as monotherapy, achieved all primary and ranked secondary endpoints in the five pivotal trials across csDMARD-naïve, csDMARD-IR, and bDMARD-IR populations. Upadacitinib 15 mg also demonstrated significantly higher rates of remission and low disease activity in all five pivotal trials, compared with placebo, methotrexate, or adalimumab. Labeled warnings of JAK inhibitors include serious infections, herpes zoster, malignancies, major cardiovascular events, and venous thromboembolic events. Short- and long-term integrated analyses showed that upadacitinib 15 mg was associated with increased risk of herpes zoster and creatine phosphokinase elevations compared with methotrexate and adalimumab but otherwise had comparable safety with these active comparators. This review suggests that upadacitinib 15 mg had a favorable benefit–risk profile. The safety of upadacitinib will continue to be monitored in long-term extensions and post-marketing studies.

     

Medical treatment of juvenile idiopathic arthritis

Juvenile idiopathic arthritis is the most common chronic autoimmune disease. The outcome of this inflammatory disease is uncertain. Patients may suffer from severe joint damage leading to mutilations as well as from extraarticular manifestations. The prognosis is variable and depends in part on the number of affected joints and the occurrence of extraarticular manifestations. Pharmacomedical treatment has changed markedly in the last decade. It consists of a combination therapy including nonsteroidal antirheumatics, glucocorticoids either systemic or intraarticular, classical disease modifying drugs like sulfasalazine and methotrexate as well as leflunomide and biologicals. These new therapeutic strategies have effected dramatic improvements also in patients with severe, so far intractable disease. The TNF inhibitors etanercept and adalimumab have succeeded in double blind controlled trials, while infliximab failed to show significant superiority over placebo. Further treatment options include inhibitors of interleukin 1 (anakinra and rilonacept), interleukin 6 (tocilizumab) and inhibitors of T-cell activation (abatacept). This review will summarize the pharmacotherapeutic options based on studies published in the literature.