Petros Efthimiou

Adult-Onset Still's Disease : Pathogenesis, Clinical Manifestations and Therapeutic Advances

Adult-onset Still’s disease (AOSD) is a rare, systemic inflammatory disease of unknown aetiology, characterized by daily high spiking fevers, evanescent rash and arthritis. Our objective was to review the most recent medical literature regarding advances in the understanding of disease pathogenesis, diagnosis and treatment. There is no single diagnostic test for AOSD, and diagnosis is based on clinical criteria and usually necessitates the exclusion of infectious, neoplastic and autoimmune diseases. Laboratory tests are nonspecific and reflect heightened immunological activity with leukocytosis, elevated acute phase reactants and, in particular, extremely elevated serum ferritin levels. Abnormal serum liver function tests are common, while rheumatoid factor and antinuclear antibodies are usually absent. Recent studies of the pathogenesis of the disease have suggested an important role for cytokines. Interleukin (IL)-1, IL-6 and IL-18, macrophage colony-stimulating factor, interferon-γ and tumour necrosis factor (TNF)-α are all elevated in patients with AOSD. Prognosis depends on the course of the disease and tends to be more favourable when systemic symptoms predominate.Treatment includes the use of corticosteroids, often in combination with immunosuppressants (e.g. methotrexate, gold, azathioprine, leflunomide, tacrolimus, ciclosporin and cyclophosphamide) and intravenous immunoglobulin. Biological agents (e.g. anti-TNFα, anti-IL-1 and anti-IL-6) have been successfully used in refractory cases. Further progress has been hampered by the rarity and heterogeneity of the disease, which has not permitted the execution of randomized controlled studies.

The Use of Canakinumab, a Novel IL-1β Long-Acting Inhibitor, in Refractory Adult-Onset Still's Disease

OBJECTIVES We describe the successful treatment of adult-onset Stills disease (AOSD) with canakinumab, a novel anti-interleukin (IL)-1β, long-acting, monoclonal antibody, on patients refractory to anakinra and rilonacept. In many cases the expected positive therapeutic effect of short-acting IL-1 inhibitors is transient or completely absent, leading to our hypothesis that their short half-life may be associated with incomplete IL-1 blockade, given the cyclic nature of the disease. METHODS We report 2 cases of AOSD resistant to short-acting IL-1 blockade, which were subsequently treated with canakinumab. A retrospective chart review was conducted of patients diagnosed with AOSD in our regional referral center. RESULTS Response to treatment was assessed by its effect on the systemic symptoms (resolution of fever and rash), polyarthritis (using the disease activity score 28--C-reactive protein score), and the levels of serum ferritin. Canakinumab demonstrated sustained efficacy in both patients as evidenced by clinical and laboratory parameters with minimal adverse reactions. CONCLUSIONS This is the first documented report of successful use of canakinumab, a novel IL-1β inhibitor, in AOSD patients refractory to traditional disease-modifying antirheumatic drugs and short- to moderate-acting IL-1 blockade. Prospective comparative studies are needed to validate canakinumabs efficacy and safety.

Complementary and alternative medicine use in rheumatoid arthritis: proposed mechanism of action and efficacy of commonly used modalities

Complementary and alternative medicine (CAM) has become popular in patients with Rheumatoid arthritis (RA) worldwide. The objective of this study is to systematically review the proposed mechanisms of action and currently available evidence supporting the efficacy of CAM modalities in relieving signs and symptoms of RA. The prevalence of CAM usage by RA patients is anywhere from 28% to 90%. Many published studies on CAM are based on animal models of RA and there is often insufficient evidence for the efficacy of CAM modalities in RA. The existing evidence suggests that some of the CAM modalities, such as acupuncture, herbal medicines, dietary omega-3 fatty acids, vitamins, and pulsed electromagnetic field show promising efficacy in reducing pain. While the use of CAM modalities for the treatment of RA continues to increase, rigorous clinical trials examining their efficacy are necessary to validate or refute the clinical claims made for CAM therapies.

Life-threatening complications of adult-onset Still's disease.

Adult-onset Still’s Disease (AOSD) since its description in 1971 has proven to be a very complex and challenging disease entity. This rare auto-inflammatory disease is classically described by the “Still’s triad” of fever, rash, and arthritis, although the atypical cases frequently outnumber the typical ones. The exact pathogenesis and etiologic factors responsible for the clinical features remain largely obscure, despite recent suggestive cytokine biology findings. Diagnosis is made on clinical grounds, following the exclusion of mimickers of infectious, autoimmune or neoplastic etiology, with the additional consideration of non-specific laboratory abnormalities such as peripheral leukocytosis and elevation of serum ferritin and other acute phase reactants. The disease manifestations are protean and can include diverse complications, affecting multiple organ systems. Moreover, the severity of the organ involvement can vary considerably, representing a wide spectrum from the self-limited to severe. The mainstay of therapy has evolved from the traditional use of corticosteroids and oral immunosupressants to the newer targeted treatments with biologic agents. The scope of this review is to alert the clinician to the existence of life-threatening AOSD complications, namely the macrophage activation syndrome, disseminated intravascular coagulopathy, thrombotic thrombocytopenic purpura, diffuse alveolar hemorrhage, and pulmonary arterial hypertension. Such knowledge may lead in earlier recognition, prompt treatment, and, ideally, improved patient outcomes.

Erratum to “Ferritin in Adult-Onset Still’s Disease: Just a Useful Innocent Bystander?”

There is an error in the citations of our previous paper as reference [51] G. Zandman-Goddard, M. Blank, P. Langevitz et al., “Antiserum amyloid component P antibodies in patients with systemic lupus erythematosus correlate with disease activity,” Annals of the Rheumatic Diseases, vol. 64, no. 12, pp. 1698–1702, 2005 should be replaced by the following references: [1] Li, X., et al., “Epidermal Growth Factor-Ferritin H-Chain Protein Nanoparticles for Tumor Active Targeting,” Small, 2012; [2] Jezequel, P., et al., “Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: A multicentric 2004 national PHRC study,” International Journal of Cancer, 2012. 131(2): p. 426–37. [3] Pitcher, J., et al., “Disruption of neuronal CXCR4 function by opioids: preliminary evidence of ferritin heavy chain as a potential etiological agent in neuroAIDS,” Journal of Neuroimmunology, 2010. 224(1-2): p. 66–71. [4] Rosen, H. R., “Placental isoferritin-associated p43 in pregnancy and breast cancer: minireview,” Neoplasma, 1996. 43(6): p. 357–62.

Ferritin in Adult-Onset Still's Disease: Just a Useful Innocent Bystander?

Background. Adult-Onset Stills Disease (AOSD) is an immune-mediated systemic disease with quotidian-spiking fever, rash, and inflammatory arthritis. Hyperferritinemia is a prominent feature, often used for screening. Methods. The key terms “ferritin” and “hyperferritinemia” were used to search PubMed and Medline and were cross-referenced with “Stills Disease.” Results. Hyperferritinemia, although nonspecific, is particularly prevalent in AOSD. While most clinicians associate ferritin with iron metabolism, this is mostly true for the H isoform and not for the L isoform that tends to increase dramatically in hyperferritenemia. In these situations, hyperferritinemia is not associated with iron metabolism and may even mask an underlying iron deficiency. We review, in systematic fashion, the current basic science and clinical literature regarding the regulation of ferritin and its use in the diagnosis and management of AOSD. Conclusion. Serum hyperferritinemia in AOSD has been described for 2 decades, although its mechanism has not yet been completely elucidated. Regulation by proinflammatory cytokines such as interleukin (IL)-1b, IL-6, IL-18, MCSF, and INF-α provides a link to the disease pathogenesis and may explain rapid resolution of hyperferritinemia after targeted treatment and inhibition of key cytokines.

Complementary and Alternative Medicine in Rheumatoid Arthritis: No Longer the Last Resort!

Complementary and alternative medicine (CAM) has become popular with consumers worldwide and accounts for significant private and public health expenditures. According to earlier reports, the prevalence of CAM use by rheumatoid arthritis (RA) patients in the United States is anywhere between 28% and 90%. Extensive use among RA patients and the limited knowledge among physicians had confirmed the need to evaluate the increasing prevalence of various CAM modalities. The primary aim of this study was to identify the incidence of CAM usage among our RA patients. Additionally, we aimed to correlate patient demographics and disease characteristics with the use of specific CAM modalities. An analysis of data extracted from our institution’s RA longitudinal registry was performed. The patients were asked to select from a list the modalities they were currently using and/or had used in the past. Of patients, 75.9% reported current or past use of CAM with >10% using 12 different modalities. Nutritional supplements and touch therapies were the most widely used overall, with mind–body therapies more prevalent among younger patients. CAM users were found to have more extra-articular manifestations and fewer comorbidities than non-CAM users. The use of CAM among RA patients is widespread with a broad spectrum of CAM modalities being used in early stages of the disease, frequently in conjunction with mainstream conventional treatments. Therefore, CAM may no longer be considered the rheumatoid patients’ last resort.

Biological targets in the treatment of rheumatoid arthritis: a comprehensive review of current and in-development biological disease modifying anti-rheumatic drugs

Enhanced understanding of the rheumatoid arthritis (RA) pathophysiology and the role of cytokines has enabled the development of innovative biological agents in the last 10 years that target specific parts of the immune response. Failure to achieve adequate response with traditional disease modifying anti-rheumatic drugs (DMARDs) and increasing evidence of ongoing radiographic deterioration of the affected joints despite seemingly clinical response were essential stimuli for the development of biologics. The current and upcoming biological agents are primarily aimed at neutralizing circulating and cell-bound pro-inflammatory cytokines, interfering in the interaction of antigen-presenting and T-lymphocytes, eliminating circulating B-lymphocytes or by interfering with the intracellular signaling mechanisms of immuno-competent cells that lead to inflammation. These agents have improved the currently available treatments due to greater efficacy, fast action and greater tolerability. However, use of these agents has also been associated with significant, although rare, adverse events and considerable cost. Therefore, these agents should be used with caution by experienced clinicians. The present work aims to provide a global and updated review of the current and in-development biological DMARDs for the treatment of RA.

Intravenous Gammaglobulin and Thalidomide May Be an Effective Therapeutic Combination in Refractory Scleromyxedema: Case Report and Discussion of the Literature

OBJECTIVES Scleromyxedema, a rare systemic disease of unknown etiology, presents with progressive dermal mucin deposition, causing skin thickening and a variety of gastrointestinal, neurologic, pulmonary, cardiac, and renal complications. Scleromyxedema is notoriously difficult to treat. Our objective was to suggest a new treatment option and to propose a novel tool, musculoskeletal ultrasound, for diagnosis and disease monitoring. METHODS We present a patient with a severe scleromyxedema with cutaneous, gastrointestinal, hematologic, and neurologic manifestations. Having failed multiple therapeutic attempts, he responded to treatment with intravenous gammaglobulin (IVIG) and oral thalidomide. Using high-frequency (13 Hz) ultrasound and electronic calipers, we obtained 3 measurements of skin thickness before and after treatment to demonstrate response to treatment. A focused review of the published literature on scleromyxedema, with an emphasis on treatment, was conducted and the results were reviewed in this article. RESULTS Following treatment with IVIG, the patient showed dramatic improvement in his clinical symptoms and remained in remission through combination IVIG infusions (2 g/kg) and oral thalidomide (150 mg/d). Literature review revealed the absence of any controlled studies for the treatment of scleromyxedema. Various agents have been proposed in case reports and small series with variable success. Emerging data on the use of IVIG or thalidomide alone have been encouraging. CONCLUSION IVIG and thalidomide in combination may be an effective novel treatment of scleromyxedema. Additionally, skin ultrasonography, a noninvasive test, may become a useful diagnostic and disease activity monitoring tool.

A novel therapeutic approach in pulmonary arterial hypertension as a complication of adult-onset Still's disease: targeting IL-6

Adult‐onset Stills Disease (AOSD), often though as the adult variant of systemic juvenile idiopathic arthritis (JIA), has an incidence of 1–3 cases per 1 million. Cardinal manifestations include fever, arthritis, skin rash, sore throat, hepatosplenomegaly and lymphadenopathy. Prolongation in diagnosing this disease results from its similarity to infectious, malignant and rheumatic diseases and lack of biomarkers. Pulmonary arterial hypertension (PAH) is a rare pulmonary complication of AOSD, and we are aware of only six cases reported in literature to date. Here we present a patient with AOSD who has developed pulmonary hypertension as a complication. We report a case of AOSD complicated by PAH treated successfully with tocilizumab, a humanized monoclonal antibody to human interleukin (IL)‐6 receptor. A Pubmed and Medline search for evidence of pulmonary hypertension in AOSD and use of IL‐6 inhibition in management was performed. Data for this study was collected from the patients chart records. No infectious or neoplastic cause of her disease was identified and after extensive diagnostic workup, the patient was diagnosed with AOSD fulfilling Yamaguchi criteria. After initiation of IL‐6 therapy the patient was followed over time to monitor the hemodynamic changes in pulmonary vasculature. Following treatment with Tocilizumab, the patient showed dramatic improvement in her clinical symptoms and remains in remission, through combination of tocilizumab (8 mg/kg), methotrexate and prednisone. Improvement of systemic symptoms, right heart catheterization (RHC) findings and the VECTRA‐DA score served as a measure of treatment response. Tocilizumab has been effective in demonstrating marked improvement in both the clinical and laboratory parameters. Tocilizumab is an effective novel treatment for AOSD with PAH. This is the first documented report of successful use of tocilizumab in AOSD patients presenting with PAH. Prospective comparative studies could help validate its efficacy and safety.