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Background: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months.Objective: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis.Design: Randomized, double-blind, placebo-controlled trial with blinded joint assessors.Setting: 13 North American centers.Patients: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs.Intervention: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months.Measurements: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months.Results: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects.Conclusions: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

Introduction: Sjögren's syndrome is a chronic autoimmune disorder that results in dry eyes and mouth. It is rarely associated with cryoglobulinemia, the agglutination of cryoglobulins at cold temperatures that leads to systemic inflammation and organ damage. We have, herein, presented a case of Cryoglobulinemic Vasculitis (CryoVas), which presents as cryoglobulinemic glomerulonephritis and Central Nervous System (CNS) vasculitis and peripheral neuropathy., Case Report: A 52-year-old woman with a past medical history of Sjögren's syndrome was admitted to the intensive care unit with severe hyponatremia, orthopnea, and progressive lower extremity weakness, and was found to have an intradural extramedullary hematoma with mass effect in the thoracic spine and diffuse hyperintense cord signal abnormality in thoracic spine suggestive of intermixed proteinaceous or hemorrhagic material. Further testing demonstrated that the patient experienced worsening neuropathy, proteinuria, hematuria, declining renal function, and the presence of cryoglobulins in the blood. After a thorough examination and a renal biopsy, the patient was diagnosed with cryoglobulinemic glomerulonephritis and cryoglobulinemic vasculitis of the spine. The patient was treated with rituximab and pulse-dose steroids, with which the patient exhibited improved renal function and resolution of a previously seen intradural hematoma on repeat MRI., Conclusion: We have, herein, discussed a rare case of cryoglobulinemic vasculitis that has led to a rare CNS manifestation and concomitant cryoglobulinemic glomerulonephritis. This suggests that clinicians should consider cryoglobulinemic vasculitis as the etiology that could manifest with multiorgan involvement, especially in patients with underlying rheumatic diseases., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Competing Interests: The authors report no conflicts of interest.

Introduction: Outcomes of treatment for patients with Lupus have shown overall improvement and benefit from the more aggressive use of immunosuppressants and biological agents through a treat-to-target approach. However, chronic musculoskeletal pain can be refractory to treatment despite the use of non-steroidal anti-inflammatory drugs, corticosteroids, and other analgesic agents, leading to patient dissatisfaction. The concept of new neural pathways from psilocybin usage has been proposed in a variety of pain syndromes; however, it is not trialed for patients with Lupus pain., Case Presentation: The patient was a 67-year-old male with positive anti-dsDNA antibody Lupus with a predominance of chronic polyarticular joint pain treated with hydroxychloroquine and non-steroidal anti-inflammatory drugs without pain relief. Pain dramatically improved after a one-time macro-dosing of 6 grams of Psilocybin cubensis in Oregon, which he expected would only provide a sense of enlightenment. After 12 months, he continued without debilitating joint pain., Conclusion: The serotonin-2A receptor's activation triggers an array of neurophysiological reactions that disrupt the functional connections in areas of the brain that are associated with chronic pain. These neuroplastic effects can generate healthy connections, resulting in long-lasting pain relief. However, this is a process that has not been fully analyzed. While there is anecdotal evidence to suggest the therapeutic benefits for autoimmune diseases, including rheumatoid arthritis and psoriasis, there is no specific research that explores its use for lupus-related pain. Since this is the first case that shows the benefit of psilocybin in a patient with Lupus, further studies on macro-dosing psilocybin to treat Lupus pain are warranted., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Primary Sjogren's syndrome (pSS) can have a myriad of presentations, ranging from mild xerostomia to more diffuse systemic involvement. It is well established that pSS is associated with a variety of pulmonary pathologies, and it is also known that pSS patients are at higher risk for lymphoma development. Here, we present an unusual case of a woman with primary Sjogren's syndrome who had both diffuse cystic lung disease as well as extranodal MALT lymphoma, successfully treated for both conditions with the CD-20 monoclonal antibody rituximab.

Cathepsin S (CTSS) activity is elevated in Sjögren's Syndrome (SS) patient tears. Here we tested whether protease inhibition and cystatin C (Cys C) levels are reduced in SS tears, which could lead to enhanced CTSS-driven degradation of tear proteins. CTSS activity against Cys C, LF and sIgA was tested in SS or healthy control tears. Tears from 156 female subjects (33, SS; 33, rheumatoid arthritis; 31, other autoimmune diseases; 35, non-autoimmune dry eye (DE); 24, healthy controls) were analyzed for CTSS activity and Cys C, LF, and sIgA levels. Cys C and LF showed enhanced degradation in SS tears supplemented with recombinant CTSS, but not supplemented healthy control tears. CTSS activity was significantly increased, while Cys C, LF and sIgA levels were significantly decreased, in SS tears compared to other groups. While tear CTSS activity remained the strongest discriminator of SS in autoimmune populations, combining LF and CTSS improved discrimination of SS beyond CTSS in DE patients. Reductions in Cys C and other endogenous proteases may enhance CTSS activity in SS tears. Tear CTSS activity is reconfirmed as a putative biomarker of SS in an independent patient cohort while combined LF and CTSS measurements may distinguish SS from DE patients.

Background: ConclusionFibromyalgia is a chronic pain disorder characterized by diffuse musculoskeletal pain, fatigue, sleep disturbance and cognitive impairment., Objective: A significant number of fibromyalgia patients do not respond adequately to the current drugs approved by the Food and Drug Administration (FDA) for fibromyalgia treatment including pregabalin, milnacipran, duloxetine. Thus, there is still a need for adjunctive therapies., Method: Naltrexone is an opioid receptor antagonist used to treat alcohol and opioid dependence. It is hypothesized that low dose naltrexone causes transient blockade of opioid receptors centrally resulting in a rebound of endorphin function which may attenuate pain in fibromyalgia., Results: Two small prospective pilot studies have previously shown that treatment with low dose naltrexone may be an effective, safe, and inexpensive treatment for fibromyalgia., Conclusion: This prospective study lends further support to the preliminary body of evidence that naltrexone is a well tolerated and likely effective treatment option in the community setting. Further large prospective controlled trials are still needed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

We present a possible important association of tumor necrosis factor-alpha inhibition (TNFa-i) and erectile function in a male patient with rheumatoid arthritis (RA). Long-standing, untreated RA may result in significant physical limitation and disability, however often overlooked is the association between RA and erectile and sexual dysfunction. Ischemic priapism is currently unrecognized as an adverse reaction associated with TNFa-i use and there have been no reported cases with adalimumab. Our patient, a 58-year-old Hispanic man, with sero-positive, erosive RA developed persistent priapism (17 days) despite multiple urologic interventions after initial adalimumab 40 mg administration. TNFa has recently been implicated as a potential factor in erectile dysfunction through its role in vascular reactivity. Excess TNFa, from active RA, may perturb intracavernosal smooth muscle and endothelial cell function; theoretically, TNFa inhibition may then causes excess local nitric oxide production and subsequent priapism. The potential role of TNFa-i in ED and risk for priapism is an important area for future study.

Purpose: The objective of this study is to compare how likely positive tuberculin skin test (TST) and T-SPOT(®).TB (TSPOT) results predict risk factors for tuberculosis in a predominantly immigrant patient population at risk of latent TB infection (LTBI) and with rheumatologic conditions requiring immunomodulatory therapy (IMT)., Methods: Prospective study conducted at a referral rheumatology clinic. Inclusion criteria included patients on various IMT, including immunosuppressive drugs that could predispose to TB progression. We studied risk factors associated with LTBI, test results, and tests' agreement., Results: We studied 101 patients. Eighty (79.2 %) were from countries where TB is prevalent and Bacille Calmette-Guérin vaccination is placed routinely. Seventy-four (73.3 %) had rheumatoid arthritis and 92 (90.7 %) were on IMT. Among patients with both TST and TSPOT results, 25 (30.9 %) were TST(+) and 20 (24.7 %) had TSPOT(+) results. Fifteen patients (18.5 %) had TST(+)/TSPOT(+) results, and 51 (63.0 %) had TST(-)/TSPOT(-) results (agreement = 81.5 %; kappa = .54 [95 % CI, .34-.74; P < .001]). Each TSPOT(+) and TST(+) results were independently associated with immigrant status and prior residence in a TB prevalent country after adjustment for immunosuppressive therapy: Adjusted OR(TSPOT+)=6.6 (95 % CI, 1.2-123.3; P = .027); and adjusted OR(TST+)=11.2 (95 % CI, 2.0-209.5; P = .003). Seven out of 10 TST(+)/TSPOT(-) cases had a TST ≥15 mm induration, including three cases with history of TST conversion., Conclusions: TST(+) and TSPOT(+) results predict risk factors associated with LTBI independent of immunosuppressive IMT. Some TST(+)/TSPOT(-) results were unlikely to be false-negatives. The combined use of TST and TSPOT appears to be a reasonable diagnostic strategy to evaluate for LTBI in this population.

Fibromyalgia (FM) is a characterized by generalized pain with widespread tender points in specific areas and is frequently accompanied by fatigue, stiffness, and a non-restorative sleep pattern. In the current retrospective study, we identified a subgroup of FM patients who had clinically important markers of inflammation. The study also explored the use of the original American College of Rheumatology (ACR) criteria in the diagnosis of FM. Our data suggested there was a distinct subset of patients with FM who had positive ESR, CRP, ANA and RF; a group that we considered representative of inflammatory FM. None of the FM patients in this study developed a documented coexisting autoimmune illness during the retrospective review period. The existence of FM subgroups further puts into question the already controversial use of either the new or old ACR classification criteria in the diagnosis of FM, as they do not address the issue of systemic inflammation which appears to be significant., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Objective: The diagnosis of Sjögren's syndrome (SS) in routine practice is largely a clinical one and requires a high index of suspicion by the treating physician. This great dependence on clinical judgment frequently leads to delayed diagnosis or misdiagnosis. Tear protein profiles have been proposed as simple and reliable biomarkers for the diagnosis of SS. Given that cathepsin S activity is increased in the lacrimal glands and tears of NOD mice (a murine model of SS), the aim of this study was to explore the clinical utility of using tear cathepsin S (CTSS) activity as a biomarker for SS., Methods: A method to measure CTSS activity in tears eluted from Schirmer's test strips was developed and validated. Schirmer's tests were performed and CTSS activity measurements were obtained in 278 female subjects, including 73 with SS, 79 with rheumatoid arthritis, 40 with systemic lupus erythematosus, 10 with blepharitis, 31 with nonspecific dry eye disease, and 12 with other autoimmune diseases, as well as 33 healthy control subjects., Results: The median tear CTSS activity in patients with SS was 4.1-fold higher than that in patients with other autoimmune diseases, 2.1-fold higher than that in patients with nonspecific dry eye disease, and 41.1-fold higher than that in healthy control subjects. Tear CTSS levels were equally elevated in patients with primary SS and those with secondary SS, independent of the Schirmer's test strip values or the levels of circulating anti-SSA or anti-SSB antibodies., Conclusion: Markedly high levels of tear CTSS activity are suggestive of SS. CTSS activity in tears can be measured in a simple, quick, economical, and noninvasive manner and may serve as a novel biomarker for autoimmune dacryoadenitis during the diagnostic evaluation for SS., (Copyright © 2014 by the American College of Rheumatology.)

Zoledronic acid is used in the treatment of osteoporosis. Giant cell artertitis may lead to vision loss. We report a case in which vision loss occurred after zoledronic acid infusion., (© 2013 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

It has been theorized that immune thrombocytopenia (ITP) is a syndrome characterized by various defects in immune regulation, resulting in a common phenotype, decreased blood platelets, and symptoms of mucocutaneous bleeding. Most often, successful treatment of the underlying connective tissue disorder with corticosteroids or other disease-modifying agents can simultaneously improve concurrent thrombocytopenia. The best evidence to date would support the targeting of treatment to the connective tissue disorder, expecting a simultaneous improvement in the platelet count. Due to the frequent relapses associated with many of the connective tissue disorders and the frequent use of immunosuppressant agents, splenectomy should be undertaken only in highly refractory patients. Differentiating the varying immunopathic etiologies that contribute to development of connective tissue disorders may lead to a better understanding of the mechanisms of thrombocytopenia in a subset of these patients. The use of target therapies to treat connective tissue disorders has the potential of reducing the risk of the development of ITP or, conversely, inducing the development of immune thrombocytopenia.

Sarcoidosis is a multisystemic disease characterized by noncaseating granulomatous infiltration, primarily of the lungs and lymphatic system. While reports of the efficacy of adalimumab in the treatment of refractory sarcoidosis have been mixed, the more widely used infliximab has demonstrated clear efficacy in this disease. The association between tumor necrosis factor (TNF)-inhibitors and noncaseating granulomas in the lung has been reported in literature. With the exception of one patient treated with adalimumab, who developed pulmonary granuloma, the remaining patients described in literature were treated with etanercept. The current case study is, to our knowledge, the first to describe adalimumab-induced noncaseating granulomas in the bone marrow of a patient being treated for rheumatoid arthritis and suggests that although TNF-inhibitors are used in the treatment of granulomatous disorders, their use should be carefully monitored as, in rare cases, TNF-inhibitors may leave sufficient cytokine activation to support granuloma formation.

Increasing awareness of the importance of aberrant B cell regulation in autoimmunity has driven the clinical development of novel B cell-directed biologic therapies with the potential to treat a range of autoimmune disorders. The first of these drugs-rituximab, a chimeric monoclonal antibody against the B cell-specific surface marker CD20-was recently approved for treating rheumatoid arthritis in patients with an inadequate response to other biologic therapies. The aim of this review is to discuss the potential use of rituximab in the management of other autoimmune disorders. Results from early phase clinical trials indicate that rituximab may provide clinical benefit in systemic lupus erythematosus, Sjögren's syndrome, vasculitis, and thrombocytopenic purpura. Numerous case reports and several small pilot studies have also been published reporting the use of rituximab in conditions such as myositis, antiphospholipid syndrome, Still's disease, and multiple sclerosis. In general, the results from these preliminary studies encourage further testing of rituximab therapy in formalized clinical trials. Based on results published to date, it is concluded that rituximab, together with other B cell-directed therapies currently under clinical development, is likely to provide an important new treatment option for a number of these difficult-to-treat autoimmune disorders.

Antiphospholipid syndrome (APS) and catastrophic antiphospholipid syndrome (CAPS) can be challenging to treat. As they are rare, clinicians are not often exposed to these complex diseases. For the patient resistant to standard treatments new therapeutic directions can be perplexing, especially in the context of ongoing thromboses and bleeding episodes. We describe 3 patients, 2 with APS and one with CAPS, resistant to conventional medications, who responded to treatment with rituximab, an anti-CD20 monoclonal antibody. Since rituximab infusion, all the patients have had stable platelet counts and no further episodes of bleeding or thromboses.

The number of new medications to treat and even prevent arthritis and osteoporosis has expanded dramatically in recent years. Where once there were only surgical options to treat such end-stage diseases, there are now treatments targeted at the early steps in musculoskeletal pathophysiology. The use of different modalities to maximize drug access to specific bone tissues has created a golden opportunity for mechanistic studies in drug delivery systems for treating osteoporosis and other musculoskeletal diseases. This theme issue provides a timely analysis of the challenges and accomplishments in delivering medicine to the target sites in the musculoskeletal system and also provides a preview of what may come in the future for musculoskeletal medicine. As the number of animal studies and clinical trials is on the rise, the possibility to prevent or even cure the aforementioned disorders has never been closer.

In addition to its well known proinflammatory effects, tumor necrosis factor-alpha (TNF-a) has complex effects on the growth, differentiation, and death of immune cells. TNF antagonists have had dramatic effects on the suppression of rheumatoid arthritis and other rheumatic inflammatory diseases. However, TNF inhibition of RA has led to an increased incidence of drug induced anti-dsDNA production, with cases of systemic lupus erythematosus as well as exacerbations of multiple sclerosis. While etanercept does not generally alter the course of Crohn's disease we describe a rare instance where this agent may have contributed to the development of clinically significant inflammatory bowel disease.

We describe a patient with a long history of familial Mediterranean fever who developed proteinuria as a result of secondary AA amyloidosis. In this patient, the inflammatory process, including recurrent attacks of arthritis, abdominal pain, nephrotic syndrome secondary to amyloidosis, and high sedimentation rate, was rapidly suppressed by treatment with infliximab and there was remarkable improvement of the proteinuria.Because TNF-alpha is a proinflammatory cytokine that plays a major role in FMF and secondary amyloid, it is an appropriate target for therapy. Our case is the first case of reactive systemic amyloidosis secondary to familial Mediterranean fever, which responded favorably to infliximab.

Objective: To determine whether synovial fluid (SF) levels and cell-surface expression of B lymphocyte stimulator (BLyS) protein and SF levels of APRIL are elevated in patients with inflammatory arthritis (IA)., Methods: Same-day blood and SF samples from 89 patients with 103 knee effusions (81 knees with IA and 22 with noninflammatory arthritis [NIA]) were evaluated for BLyS protein and APRIL levels by enzyme-linked immunosorbent assay. Blood and SF mononuclear cells were double-stained for surface BLyS protein and surface CD14 (monocyte marker) and were analyzed by flow cytometry. Complete blood cell counts and SF nucleated cell counts were performed by the clinical hematology laboratory., Results: BLyS protein levels were higher in SF than in corresponding serum samples from both IA and NIA patients. SF BLyS protein levels, but not surface expression of BLyS protein, were disproportionately elevated in IA patients. APRIL levels were higher in SF than in corresponding serum samples from most IA patients but not NIA patients. SF BLyS protein and APRIL levels correlated with each other, and each correlated with SF monocyte, lymphocyte, neutrophil, and total nucleated cell counts. Although SF and serum BLyS protein levels correlated with each other, SF and serum APRIL levels did not, suggesting that SF BLyS protein levels are more dependent upon systemic factors than are SF APRIL levels. Moreover, in 8 patients who underwent sequential arthrocenteses, changes in SF BLyS protein levels did not immutably parallel changes in SF APRIL levels, indicating their differential regulation., Conclusion: BLyS protein and APRIL are locally produced in inflamed joints. Their respective SF levels are differentially regulated, suggesting that they serve different functions. Together, their local production may foster survival and/or expansion of B cells that produce pathogenic autoantibodies and/or promote local T cell activation and consequent joint destruction.

Objective: To analyze synovial fluid (SF) for the presence of Neisseria gonorrhoeae DNA using the polymerase chain reaction (PCR)., Methods: We used a modified, nested PCR to detect the presence of N gonorrhoeae DNA in 41 samples of SF obtained from 10 patients with clinical gonococcal arthritis whose SF samples were sterile by culture and from 27 controls, including 11 patients with Reiter's syndrome. Results obtained using this method were compared with those obtained using the GEN-PROBE system, an RNA-DNA hybridization technique., Results: With nested PCR, N gonorrhoeae DNA was detected in 11 of 14 SF samples obtained from patients with culture-negative clinical gonococcal arthritis but in none of the 11 SF samples from Reiter's syndrome patients. The specificity of this technique was 96.4%, with a sensitivity of 78.6%. The rate of false-positive results was 3.6%. The GEN-PROBE technique was unable to detect N gonorrhoeae ribosomal RNA in any of the samples., Conclusion: These findings demonstrate the potential utility of the PCR in confirming the clinical diagnosis of gonococcal arthritis as well as providing insight into the pathogenesis of this disorder in patients whose SF are sterile by standard culture techniques. PCR may also prove helpful in differentiating N gonorrhoeae arthritis from acute Reiter's syndrome.