Rheumatoid Arthritis: Smolen JS

Schett G, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna, Austria. · Curr Pharm Des. · Pubmed #16178762 No free full text.

Abstract: In chronic arthritis synovial inflammation is usually accompanied by bone erosion. Due to resulting structural damage, bone erosion is major reason for disability of RA patients. Thus, drug therapy in arthritis is not only focussed on the control of synovial inflammation but also on preserving bone from structural damage. Bone erosion in arthritis is a consequence of synovial osteoclast formation. Therapeutic approaches, which interfere with synovial osteoclastogenesis and/or osteoclast activation, are therefore of great interest. This review describes the pathomechanism of arthritic bone erosion, describes its cellular and molecular players and gives insights in current therapeutic tools to inhibit this process. Effects of blockade of tumor necrosis factor, interleukin-1 and receptor activator of NF-kB ligand are discussed. Arthritis and bone loss are two related conditions but they are not necessarily linked to each other. Thus, in case of short-lasting and self-limited disease, structural damage is highly unusual. One of the most intriguing examples is viral arthritis, which as in case of parvovirus infection is a polyarticular disease closely mimicking rheumatoid arthritis. However, parvoviral arthritis is always a self-limited condition and resolves without any structural damage. In contrast, chronic forms of arthritis, such as psoriatic arthritis or rheumatoid arthritis (RA) are usually destructive and lead to alteration of joint structure and functional impairment.

Smolen JS, Redlich K, Zwerina J, Aletaha D, Steiner G, Schett G. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Austria. · Clin Rev Allergy Immunol. · Pubmed #16129908 No free full text.

Abstract: Therapy of rheumatoid arthritis (RA) aims at interfering with the disease process, namely inflammation and destruction of the joints, and thus at preventing long-term disability. Proinflammatory cytokines play a decisive role in the generation of the inflammatory and destructive response. Aside from traditional disease-modifying anti-rheumatic drugs and tumor necrosis factor-blocking agents, a number of targeted therapies are currently in evaluation, such as abatacept (interfering with co-stimulation), rituximab (an anti-B-cell agent) and tocilizumab (an anti-interleukin-6 receptor antibody). In phase II trials, all these agents have resulted in significant clinical improvement, and phase III trials have been partly completed with similar results and are partly on the way. Because none of these agents lead to good clinical responses in all patients and many patients have only relatively low degrees of response, it will still be a challenge to find the best therapeutic paths to combat the "inflammatory house of cards" of RA.

Zwerina J, Redlich K, Schett G, Smolen JS. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Ann N Y Acad Sci. · Pubmed #16127012 No free full text.

Abstract: Although considerable progress has been made by adequate treatment with traditional disease-modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-15 (IL-15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies ("biologicals"). Blocking TNF or also, to some extent, IL-1 has proved beneficial in DMARD-resistant RA patients in multiple clinical trials. Along with clinical improvement, TNF blockade has been shown to halt radiographic disease progression, a major risk factor for disability. Recently, clinical trials have shown a significant therapeutic benefit of biological inhibitors of IL-6, and also of IL-15, with an efficacy comparable to that of TNF blockers. All these agents are particularly efficacious when combined with methotrexate. Although clinical remission is difficult to achieve even with anticytokine treatment, these drugs offer the potential to decrease disease activity and improve quality of life in a majority of RA patients, and it is conceivable that combinations of biological therapies may pave the path to even better success, which ultimately is remission or even cure.

Aringer M, Steiner G, Smolen JS. · Department of Rheumatology, Internal Medicine III, Medical University of Vienna, AKH, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Rheum Dis Clin North Am. · Pubmed #16084315 No free full text.

Abstract: For patients who have combined features of rheumatoid arthritis, the limited cutaneous form of systemic sclerosis, and inflammatory myopathies, the concept of mixed connective tissue disease (MCTD) often helps to predict and diagnose organ problems and to educate the patient accordingly. With high titer IgG antibodies to U1 ribonucleoprotein (U1-snRNP), this concept is supported by a specific serologic marker, and autoantibodies to U1-snRNP and to heterogeneous nuclear ribonucleoprotein (hnRNP)-A2 display MCTD specificity with regard to the recognized epitopes. In addition, the association of MCTD with HLA-DR4 distinguishes it from systemic erythematosus lupus and systemic sclerosis, and speaks to its being a disease entity, rather than a mixture of yet undifferentiated collagen vascular diseases. The authors believe that the concept is useful in daily practice and accurate in the idea that MCTD constitutes a disease entity of its own.

Kalden JR, Antoni C, Alvaro-Gracia JM, Combe B, Emery P, Kremer JM, Strand CV, Van Riel P, Smolen JS. · Medizinische Klinik III, Institute for Clinical Immunology, Erlangen, Germany. · J Rheumatol. · Pubmed #16078347 No free full text.

Abstract: An Expert Panel Meeting was held in May 2004 to assess experience with combination therapy with leflunomide and biological agents in the treatment of rheumatoid arthritis (RA), to identify both optimal use of such combinations and precautions for use. Eleven published prospective or retrospective studies were reviewed, principally evaluating combination of leflunomide with infliximab, as well as patient registry data. Available data suggest that combination therapies are more efficacious than monotherapies, reflecting the complementarity of mechanisms of action. Information on side effects remains contradictory, and tolerability of these combinations may vary between different patient groups. In some studies, tolerability is equivalent to that seen with monotherapy; in others a high rate of adverse events has led to frequent treatment discontinuation. Dermatological reactions may be a specific side effect of these combination therapies. Combination therapy is considered justified for treatment of patients diagnosed early who are at risk for rapid progression and for patients who fail to respond to monotherapy. The majority of participants favored adding biological agents to a previously established leflunomide monotherapy rather than starting both treatments simultaneously. On the other hand, combination therapy should be considered with caution in patients with a history of treatment failure, with hepatic comorbidity, or with other autoimmune disease, and in immunocompromised patients. When considering initiation of combination therapy, it is important to provide full information to the patient on the potential benefits and risks of such treatment and to integrate patients as far as possible into the decision-making process.

Schett G, Herak P, Graninger W, Smolen JS, Aringer M. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. · J Clin Microbiol. · Pubmed #15872306 links to  free full text

Abstract: Listeriosis can be a cause of infectious arthritis. Here, we present a case of articular listeriosis in a patient with rheumatoid arthritis receiving treatment with etanercept, a tumor necrosis factor antagonist. We review the literature of articular listeriosis and discuss the role of tumor necrosis factor blockade in precipitating listeriosis.

Smolen JS, Aletaha D, Machold KP. · Division of Rheumatology, Internal Medicine III, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Best Pract Res Clin Rheumatol. · Pubmed #15588977 No free full text.

Abstract: Rheumatoid arthritis (RA) therapy rests primarily on the use of disease-modifying antirheumatic drugs (DMARDs). It has been unequivocally shown that DMARD therapy early in the course of RA retards progression of damage and disability to a larger degree compared with delayed institution; the most effective DMARD is methotrexate (MTX). Moreover, combination therapy including intermediate to high doses of glucocorticoids and combinations of MTX with tumour necrosis factor blockers are more effective than monotherapies. However, early DMARD treatment requires early referral of patients and early diagnosis. This is hampered by the current lack of classification criteria for early RA, since the aim is to prevent destruction from occurring, while RA is typically characterized by the presence of erosions. Novel treatment strategies and therapeutic agents allow us to aim for remission rather than improvement of disease activity. Whether a 'window of opportunity' exists during which effective therapy might lead to cure is still an open issue and will be the focus of clinical trials in the near future.

Smolen JS, Hayer S, Schett G, Redlich K, Aringer M, Kollias G, Wagner E, Steiner G. · Medical University Vienna. · Autoimmun Rev. · Pubmed #15309784 No free full text.

This publication has no abstract.

Kalden JR, Smolen JS, Emery P, van Riel PL, Dougados M, Strand CV, Breedveld FC. · Department of Internal Medicine III, Universitaet Erlangen-Nuremberg, Erlangen, Germany. · J Rheumatol Suppl. · Pubmed #15170905 No free full text.

Abstract: In most studies of disease modifying antirheumatic drug therapy, in combination with either leflunomide or biological agents, patients are given an additional agent after they have failed treatment with methotrexate (MTX). This review of clinical studies shows that leflunomide is clinically efficacious and well tolerated when added to either sulfasalazine or MTX, as both an initial and ongoing treatment for rheumatoid arthritis (RA). Experience in combining leflunomide with biological agents is limited to a small number of open-label studies with infliximab. According to the opinion obtained at an International Expert Panel Meeting held in Paris in May 2003, leflunomide can be used in combination therapy: 61% of the Expert Panel would use leflunomide with MTX, 71% with sulfasalazine, 43% with infliximab, 33% with adalimumab, 19% with etanercept, and 38% with anakinra. The Expert Panel stated that the combination of leflunomide and infliximab warrants a prospective, randomized, controlled trial in patients with incomplete clinical responses to leflunomide monotherapy, provided leflunomide is started first, without a loading dose, and infliximab is added after good tolerability to leflunomide has been established. The Expert Panel concluded that combination therapy with leflunomide has a place in the treatment of RA. Caution is advised, however, when using combination treatments and, therefore, the patient's safety should be carefully monitored.

van Riel PL, Smolen JS, Emery P, Kalden JR, Dougados M, Strand CV, Breedveld FC. · Department of Rheumatology, University Medical Centre Nijmegen, Nijmegen, The Netherlands. · J Rheumatol Suppl. · Pubmed #15170904 No free full text.

Abstract: The safety profile of leflunomide in the treatment of rheumatoid arthritis has been well documented in clinical trials, postmarketing surveillance, and epidemiological studies. Both postmarketing surveillance and epidemiological study results are consistent with the safety profile of leflunomide reported in clinical trials, and no increased risk was observed with leflunomide, compared with other disease modifying antirheumatic drugs; these studies have allowed a more precise representation of the incidence of adverse events occurring with leflunomide under normal conditions of care. The most common leflunomide-associated adverse events include diarrhea, elevated liver enzymes, alopecia, and rash. Ninety-five percent of the Expert Panel considered the adverse events associated with leflunomide to be manageable. If an adverse event required treatment to be stopped, many of the experts would consider subsequently restarting leflunomide. For minor adverse events, it was suggested that the physician might also consider using cholestyramine or charcoal to determine if the side effect is dose-related and, if it was, reduce the leflunomide dose accordingly. In addition to informing patients about the likelihood of side effects, it is important to emphasize that their incidence appears to diminish with continued treatment. It is also important to adequately support patients who are experiencing side effects and involve them in their disease management, for example, by offering the choice of reducing the leflunomide dose and/or having symptomatic treatment. Other patient management recommendations in this review reflect the views of the majority of participants as expressed in the meeting.

Smolen JS, Emery P, Kalden JR, Van Riel PL, Dougados M, Strand CV, Breedveld FC. · Division of Internal Medicine III, Division of Rheumatology, Medical University of Vienna, Vienna, Austria. · J Rheumatol Suppl. · Pubmed #15170903 No free full text.

Abstract: This expert review of results from the leflunomide phase II and III clinical trials database demonstrates that leflunomide meets all 3 goals desired of disease modifying antirheumatic drug (DMARD) therapy: reducing the signs and symptoms of the disease; inhibiting structural damage; and improving physical function. Further, leflunomide has a rapid onset of action, sustained efficacy, and is effective in early and late disease, regardless of whether patients have received other DMARD previously. The consistent efficacy of leflunomide across phase III clinical trials is confirmed by the findings from clinical practice. Experts agreed that it is important to observe a patient under leflunomide monotherapy for at least 3-4 months before assessing efficacy. It is possible to start maintenance therapy, with either a daily dose of leflunomide 10 mg, subsequently changing to 20 mg, or the reverse. The decision to use a loading dose when initiating leflunomide therapy depends primarily on the balance between the tolerability and rapid efficacy associated with a loading dose, and the balance desired for an individual patient. In general, the use of both maintenance and loading doses requires a flexible approach to the treatment of rheumatoid arthritis. During the first few weeks of leflunomide therapy, patient dropout can be avoided by using prednisolone rather than a loading dose. Moreover, to ensure good tolerability and compliance in patients receiving a loading dose, information and adequate support should be provided throughout treatment.

Pincus T, Yazici Y, Sokka T, Aletaha D, Smolen JS. · Division of Rheumatology and Immunology, Vanderbilt University School of Medicine, 203 Oxford House, Box 5, Nashville, TN 37232-4500, USA. · Clin Exp Rheumatol. · Pubmed #14969073 No free full text.

Abstract: The two major advances over the 1990s in the treatment of rheumatoid arthritis (RA) were a shift in strategy from a "pyramid", in which disease modifying anti-rheumatic drugs (DMARDs) were deferred for several years, to the early aggressive use of DMARDs and widespread acceptance of methotrexate as the DMARD with the most long-term effectiveness and safety. Methotrexate courses are continued far longer than those of any other DMARD, an excellent indicator of greater effectiveness and safety. In one recent series, methotrexate was the first DMARD used in more than 80% of patients with RA. Studies which document the superiority of combinations of methotrexate with biological agents to methotrexate monotherapy select for only a minority of contemporary patients with RA who have severe disease activity and incomplete responses to methotrexate. In one locale, only 5% of patients met criteria for the Anti-Tumor Necrosis Factor Trial in RA with Concomitant Therapy (ATTRACT) trial and only 30% met the criteria for the Early Rheumatoid Arthritis (ERA) trial. In studies comparing methotrexate directly with biological agents, the biological agents have greater efficacy in patients with very severe disease, but the best results are seen in patients who take a combination of methotrexate and biologic agents. These data establish that methotrexate is the anchor drug and probably should be the first DMARD used in the majority of patients with RA at this time.

Aletaha D, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #14969071 No free full text.

Abstract: The concept of early and aggressive therapy of rheumatoid arthritis (RA) has been well documented in the past years. It includes immediate DMARD institution after diagnosis, the use of the most effective DMARDs, and rapid switching of regimens if a level of disease activity close to remission is not achieved. In this review we briefly explore to what degree this new concept has been implemented in routine clinical care. Based on an observational dataset comprising 3342 DMARD courses, we present evidence of a change in DMARD patterns in newly diagnosed RA patients towards a higher prescription rate of more aggressive drugs like methotrexate (MTX), as well as a decreasing lag time until MTX was instituted in RA patients over the years. One consequence of recent changes in therapeutic strategies is that comparative analyses of formerly versus recently employed DMARDs will be considerably biased in observational studies. By contrast to changes in DMARD usage, survey data show neither a shortening of referral time nor a change in the approach to diagnose early RA. These data indicate a need for more dissemination of the early arthritis concept.

Machold KP, Nell VP, Stamm TA, Eberl G, Steiner G, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Austria. · Clin Exp Rheumatol. · Pubmed #14969061 No free full text.

Abstract: The Austrian Early Arthritis Registry (Austrian Early Arthritis Action, EAA) enrols and follows patients with inflammatory arthritis of very short (< 12 weeks) duration. Currently, data on 375 patients (almost 2000 individual follow-up examinations) have been entered into the EA database. Evaluations of data from 182 patients with a follow-up of at least one year are available. 65% of these patients have RA, as diagnosed using the ACR classification criteria in a cumulative fashion. Approximately 15% of these patients still have no established diagnosis and are being carried forward and observed as cases of "undifferentiated arthritis". In RA patients, the mean DAS 28 decreased significantly from an initial mean score of 5.5 (high disease activity) into the range of low disease activity. At the end of one year a DAS 28 of < 3.2 was observed in 52% of the RA patients. Radiological progression in these RA patients, who also received treatment very early, appears to be less severe than in other cohorts, although direct comparisons are impossible due to different methods of patient selection. In addition, the serological data from our cohort in cooperation with other study groups will allow development and validation of possible prediction algorithms for early arthritis patients which could improve the diagnostic and therapeutic approach to this patient group.

Redlich K, Schett G, Steiner G, Hayer S, Wagner EF, Smolen JS. · University of Vienna, Vienna, Austria. · Arthritis Rheum. · Pubmed #14673982 links to  free full text

This publication has no abstract.

Smolen JS. · Department of Rheumatology, Vienna General Hospital, University of Vienna, Vienna, Austria. · Drugs Today (Barc). · Pubmed #14668927 No free full text.

Abstract: The goals for the treatment of rheumatoid arthritis have changed from slowing the disease process only after a definitive diagnosis is made, to intervening early to minimize disease activity and achieve and maintain remission. To meet the new goals, both monotherapy and combination therapy must be administered not only early but aggressively, and aggressive therapy must be sustained. In addition, the efficacy of this treatment design can only be achieved if disease activity is monitored.

Aletaha D, Smolen JS. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Vienna General Hospital, Waehringer Guertel 18-20, A-1090 Vienna, Austria. · Curr Rheumatol Rep. · Pubmed #14609484 No free full text.

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Furst DE, Breedveld FC, Kalden JR, Smolen JS, Burmester GR, Dougados M, Emery P, Gibofsky A, Kavanaugh AF, Keystone EC, Klareskog L, Russell AS, van de Putte LB, Weisman MH, Kavenaugh AF. · University of California, UCLA, Rheumatology, Division Los Angeles, USA. · Ann Rheum Dis. · Pubmed #14532138 links to  free full text

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Schett G, Redlich K, Smolen JS. · Department of Internal Medicine III, Division of Rheumatology, University of Vienna, Austria. · Arthritis Res Ther. · Pubmed #12932284 links to  free full text

Abstract: Bone erosion is a hallmark of rheumatoid arthritis. Recent evidence from experimental arthritis suggests that osteoclasts are essential for the formation of local bone erosions. Two essential regulators of osteoclastogenesis have recently been described: the receptor-activator of nuclear factor kappa B ligand, which promotes osteoclast maturation, and osteoprotegerin (OPG), which blocks osteoclastogenesis. The present review summarizes the current knowledge on the role of osteoclasts in local bone erosion. In addition, the role of OPG as a therapeutic tool to inhibit local bone erosion is addressed. Finally, evidence for OPG as an inhibitor of systemic inflammatory bone loss is discussed.

Smolen JS, Steiner G. · Division of Rheumatology, Department of Internal Medicine III, University of Vienna, Austria. · Nat Rev Drug Discov. · Pubmed #12776222 No free full text.

Abstract: Recent years have seen considerable advances in our understanding of both the clinical and basic-research aspects of rheumatoid arthritis. Clinical progress has come from a better recognition of the natural history of the disease, the development and validation of outcome measures for clinical trials and, consequently, innovative trial designs. In parallel, basic research has provided clues to the pathogenic events underlying rheumatoid arthritis, and advances in biotechnology have facilitated the development of new classes of therapeutics. Here, we summarize the fruits of these advances: innovative approaches to the use of existing, traditional disease-modifying antirheumatic drugs; novel agents approved very recently; and further avenues that are presently under investigation or which are of more distant promise.

Machold KP, Smolen JS. · Department of Internal Medicine 3, Vienna University, Währinger Gürtel 18-20, A-1090 Vienna, Austria. · Expert Opin Biol Ther. · Pubmed #12662147 No free full text.

Abstract: Tumour necrosis factor alpha (TNF-alpha) is a pro-inflammatory cytokine with various roles in inflammatory processes. Several TNF blockers are currently approved for use in rheumatoid arthritis (RA) as well as in other inflammatory arthropathies. The latest of these compounds is the human monoclonal antibody, adalimumab, which was obtained using phage display technology and successfully produced in a mammalian expression system. Clinical application of this compound led to significant improvement in patients suffering from RA, both as monotherapy and in combination with various disease modifying antirheumatic drugs (DMARDs), including methotrexate (MTX). Moreover, radiographic progression is significantly inhibited and quality of life improved. This article summarises the available information.

Dougados M, Smolen JS. · Hĵpital Cochin, Department of Rheumatology, Paris, France. · J Rheumatol Suppl. · Pubmed #12435165 No free full text.

Abstract: Treatments for rheumatoid arthritis (RA) have involved a variety of single agent and combination therapies with one paramount goal, to slow disease progression and bone destruction. However, data indicate that not all drug combinations are equally efficacious in all patients with RA, and toxicity levels can be difficult to manage. In addition to these concerns, studies are difficult to compare because of methodologic differences and differing drug doses and schedules, for example. To more accurately discern how to best manage early RA, and because treating RA within 3 months of diagnosis appears crucial for improved outcomes, this review summarizes studies that compared combination to monotherapies in early RA, while attempting to consider factors that could complicate the results. These reports utilized disease modifying antirheumatic drugs (DMARD) with known efficacy among patients with RA, but more importantly a number also used varying levels of glucocorticoids as well. Collectively, these data are beginning to shed light on how to best treat early RA, suggesting that DMARD work best when given very early.

Furst DE, Breedveld FC, Kalden JR, Smolen JS, Antoni CE, Bijlsma JW, Burmester GR, Cronstein B, Keystone EC, Kavanaugh A, Klareskog L. · University of California, Los Angeles, CA, USA. · Ann Rheum Dis. · Pubmed #12379612 links to  free full text

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Simon LS, Smolen JS, Abramson SB, Appel G, Bombardier C, Brater DC, Breedveld FC, Brune K, Burmester GR, Crofford LJ, Dougados M, DuBois RN, Fitzgerald GA, Frishman W, García Rodríguez LA, Hochberg MC, Kalden JR, Laine L, Langman MJ, Prescott SM, van de Putte LB, Whelton A, White WB, Willaims GH. · Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. · J Rheumatol. · Pubmed #12136912 No free full text.

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Huizinga TW, Machold KP, Breedveld FC, Lipsky PE, Smolen JS. · Leiden University Medical Center, Leiden, The Netherlands. · Arthritis Rheum. · Pubmed #12115216 links to  free full text

This publication has no abstract.