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OBJECTIVE There is an unmet need for a reliable biomarker for the differentiation of axial spondyloarthritis (AxSpA) from its mimickers. Serum levels of interleukin-22 (IL-22) have previously been found to be significantly elevated in patients with AxSpA compared with healthy individuals or persons with osteoarthritis. METHODS Consecutive patients with established or suspected AxSpA were enrolled. The clinical data, as well as results of laboratory and imaging studies, were acquired from patients' charts. The final diagnosis of definite or probable SpA, or an alternative diagnosis, was determined, and the serum levels of IL-22 were examined by enzyme-linked immunosorbent immunoassay. RESULTS Interleukin-22 levels were significantly higher in patients with definite AxSpA (29 patients) compared with patients with alternative diagnoses (14 patients) and healthy volunteers (16 individuals; P

To evaluate the feasibility of the autoinflammatory disease activity index (AIDAI) as a tool to assess disease activity in patients with hereditary recurrent fever syndromes (HRFs) treated with canakinumab.Patients with active colchicine-resistant familial Mediterranean fever (crFMF), mevalonate kinase deficiency (MKD), or tumor necrosis factor receptor-associated periodic syndrome (TRAPS) were enrolled in the phase III CLUSTER study and asked to complete the AIDAI questionnaire daily. All patients included in the analysis were treated with canakinumab, but regimens and periods of treatment varied per study protocol. The AIDAI for each patient was calculated weekly over the first 40 weeks of study, based on the diaries completed over 30 days. Disease-specific cut-off AIDAI values for inactive disease were calculated in a ROC analysis by comparing AIDAI scores with the occurrence of clinically inactive disease, based on the physician global assessments of disease activity and the occurrence of flares.Sixty patients with crFMF, 70 with MKD, and 43 with TRAPS were included in the analysis. Median AIDAI scores were high during the first 4 weeks for the three disease cohorts, and decreased afterwards, with some differences between disease cohorts. AIDAI values of 12.0, 9.6 and 15.5 were obtained as the most optimal thresholds to discriminate patients with inactive disease, with sensitivity and specificity values mostly over 75%.The AIDAI allows to discriminate between patients with active and inactive HRFs, and can be used in clinical practice to monitor the disease course of patients and the effect of medications.

Crowned dens syndrome (CDS) is defined as acute cervical or occipital pain due to a local inflammatory reaction related to calcifications in the ligaments surrounding the odontoid process. Virtually, all previous descriptions of CDS have related to calcium pyrophosphate dehydrate (CPPD) arthropathy.We prospectively identified a total of twenty-four consecutive inpatients with Crowned dens syndrome from January 2016 to December 2017 in our institution.All patients (age range 54 to 87 years, 67% females) presented with acute onset pain in the upper neck and/or occiput accompanied with extreme neck stiffness. Most patients (79%) had elevated inflammatory markers. Four patients underwent temporal artery biopsy, which was negative for arteritis in all cases, and one was subjected to lumbar puncture, which was non-contributory. Seventeen patients (71%) had known rheumatic disease on presentation: 10 patients had the diagnosis of calcium pyrophosphate dehydrate arthropathy, 3 patients had ankylosing spondylitis, 2 patients had rheumatoid arthritis, 1 patient had Behcet's disease, and 1 suffered from Familial Mediterranean Fever. In 4 more patients, crowned dens syndrome was the presenting symptom of calcium pyrophosphate dehydrate disease. All patients were treated with glucocorticoids as 0.5 mg/kg prednisone plus colchicine 0.5 mg bid resulting in dramatic improvement in both clinical (head/neck pain alleviated and cervical spinal mobility regained) and laboratory measures.Crowned dens syndrome should be considered, and craniocervical junction imaged in the context of acute cervical or occipital pain with stiffness and elevated inflammation markers not only in patients previously diagnosed with calcium pyrophosphate dehydrate arthropathy but also in diverse clinical settings.Key Points• This report highlights that crowned dens syndrome should be considered in various clinical setting besides calcium pyrophosphate dehydrate (CPPD) arthropathy.• Vigilance to this syndrome allows rapid treatment and may spare the patient unnecessary invasive procedures (i.e., temporal artery biopsy or lumbar puncture).

Objective Lysyl oxidase (LOX) is an extracellular enzyme that cross-links collagen fibrils. LOX was found to be increased in serum of SSc patients and was suggested to be related to skin fibrosis, yet a vascular source of LOX has been demonstrated in idiopathic pulmonary arterial hypertension (iPAH). We aimed to validate elevated LOX serum levels in SSc and to study its correlation with clinical characteristics and investigate its main source at the tissue level. Methods A total of 86 established SSc patients were compared with 86 patients with very early diagnosis of systemic sclerosis (VEDOSS), 110 patients with primary RP (PRP) and 80 healthy controls. LOX serum levels were determined by ELISA. Five lung and 12 skin biopsies from SSc patients were stained for LOX and compared with controls. Results Serum levels of LOX in SSc were significantly higher than in VEDOSS, PRP and healthy controls (P < 0.001). LOX inversely correlated with the diffusing capacity of the lung for carbon monoxide diffusing capacity (DLCO) in diffuse SSc (r = −0.376, P = 0.02). Patients with moderate to severe estimated systolic PAH had higher LOX levels (P < 0.01). Lung biopsies demonstrated intense LOX staining in SSc patients with PAH that was predominantly located in the endothelium of the remodelled pulmonary vessels. Conclusion Serum LOX levels are increased in established SSc and inversely correlate with the DLCO. LOX is elevated in patients with moderate to severe PAH and is located in the proliferating endothelium in lung arterioles, suggesting a possible role for LOX in SSc-associated PAH.

Systemic sclerosis (SSc) is an autoimmune disease in which environmental exposure to substances and agents may trigger disease onset or exacerbation. The most fatal complication of SSc is scleroderma renal crisis (SRC), the incidence of which is 2-3%. SRC usually occurs in the first 5 years from disease onset in diffuse-SSc patients with anti-topoisomerase 1 (ATA) or RNA polymerase 3 antibodies [1]. Other risk factors for SRC are pericardial effusion, tendon friction rub and steroid use. We report herein a case of scleroderma renal crisis (SRC), following covid-19 infection, in a limited-SSc patient who was in long remission prior to the infection without any risk factors for SRC. the temporal relationship and lack of other risk factors combine to suggest covid-19 infection as a possible trigger for SRC. We discuss the shared pathophysiology of covid-19 infection and SRC, including, vasculopathy, endothelial activation, hypercoagulability, cytokines release as interleukin 6, that may explain the possible role of covid-19 infection, as a trigger for SRC in SSc patients.

To the Editor: Systemic sclerosis (SSc) is a complex disease involving multiple pathophysiological pathways: autoimmunity, vasculopathy, and fibrosis, all of which are interrelated. Most of the damage consists of skin and lung fibrosis, and is accumulated within the first 2 years of disease in rapidly progressive patients with a serology of anti-SCL-70 or anti–RNA polymerase III (RNAP3)1. Indeed, this group of patients carry a great risk of morbidity and excess mortality. A combination “induction” therapy at an early stage—a window of opportunity—in which it is still possible to change the course of disease in this group of patients, is logical. We report herein our recent experience with early upfront combination therapy for progressive SSc, directed at different aspects of disease: iloprost for treating vasculopathy, rituximab (RTX) for blocking B cells, and mycophenolate mofetil (MMF) for inhibiting T cells. Until recently, the gold … Address correspondence to Dr. D. Rimar, Rheumatology Unit, Bnai Zion Medical Center, POB 4940, Haifa, 31048 Israel. Email: doronrimar{at}gmail.com.

Background Polyarteritis Nodosa (PAN) is a necrotizing vasculitis predominantly affecting medium and small size arteries (1). Cyclophosphamide, a drug with narrow therapeutic range and poor safety profile, constitutes the treatment of choice for PAN vasculitis with major organ involvement. (2) Objectives To describe our clinical experience in treating refractory PAN with infliximab (a TNF inhibitor), a drug with good tolerability and better safety profile than cyclophosphamide. Methods Twenty-six PAN patients were admitted to our rheumatology unit between 2006 and 2017, of whom 9 patients, with severe and refractory disease, were treated with infliximab after failure of standard treatment. We describe herein the patients’ characteristics, clinical manifestations, severity and response to infliximab treatment and review the current literature. Results Complete remission was defined as the absence of features of active disease and withdrawal of prednisone therapy. Significant improvement was defined as clinical improvement and prednisone dose reduction of at least 50% or a 50% reduction in immune modulatory medications other than prednisone. After 4 months of treatment, 8/9 (89%) patients achieved significant improvement, with two of them achieving complete remission. Conclusion We suggest anti TNF agents, and in particular infliximab, are relatively safe and efficacious treatment options in refractory PAN A randomized controlled trial should be done in order to objectively evaluate infliximab in PAN. References [1] Jennette JC, Falk RJ, Bacon PA, Basu N, Cid MC, Ferrario F, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013; 65:1-11. [2] De Virgilio A, Greco A, Magliulo G, Gallo A, Ruoppolo G, Conte M, Martellucci S, de Vincentiis M. Polyarteritis nodosa: A contemporary overview. Autoimmun Rev. 2016; 15:564-70. Disclosure of Interests None declared

Background:Angiogenesis is an important contributor to the development of Rheumatoid arthritis (RA). Tocilizumab (TCZ), an anti-IL-6 receptor antibody, is an immunosuppressant used in the treatment of RA patients, but its effects on angiogenesis and the molecular mechanisms regulating new blood vessel formation are not fully elucidated.Objectives:To evaluate the concentrations of pro- and anti-angiogenic factors in serum samples of RA patients, before and after the initiation of TCZ treatment and to explore in an in vitro co-culture system the mechanisms of TCZ action.Methods:We evaluated the concentrations of EMMPRIN, VEGF, MMP-9, IL-6, NGAL, endostatin and thrombospondin-1 (Tsp-1) using commercial ELISA kits from 40 RA patients, before and 4 months after the initiation of TCZ treatment. The levels of secreted EMMPRIN, VEGF MMP-9 and Tsp-1 were measured in an in vitro co-culture system of HT1080 fibroblasts and U937 monocytes with and without addition of anti-EMMPRIN blocking antibody. In the tube formation assay serum samples and supernatnats from the co-cultures were added to endothelial layer. Images were obtained after 6 hours of incubation and the number of closed lumens were counted in two separate fields. In the wound assay, supernatants from the co-cultures, with or without the addition of the anti-EMMPRIN antibody were added to the endothelial layer after scratching. The scratch site area was measured immediately and compared to the area after 24 hours of incubation to assess the distance of cell migration.Results:Study population included 40 RA patients, 33 (82.5%) females, mean age of 57.5±11.1 years, disease duration of 7.7±5.6 years, and 53.9% positive for rheumatoid factor initiating treatment with TCZ. In this patient cohort, 25/40 (62.5%) patients were classified as “responders” according to EULAR criteria.Following 4 mounts of treatment, statistically significant reductions in the levels of EMMPRIN/CD147 (p=0.035), without significant changes in serum levels of MMP-9, VEGF, MMP-3 and MMP-7 and of the anti-angiogenetic factors Tsp-1 and endostatin were found. A statistically significant decrease in the ratio between the pro-angiogenic factor EMMPRIN and the anti-angiogenic factor Tsp-1 that was calculated for each patient 4 months after initiating TCZ was found(p=0.031). The decrease in angiogenesis was manifested by the reduced number of closed lumen tube-like structures formed by EaHy926 endothelial cell line after incubation with serum samples 4 months after initiation of TCZ, relative to the number of closed lumens formed prior to TCZ initiation (p=0.007). The ratio between EMMPRIN and Tsp-1 was significantly reduced in the responding patients versus non-responders (p=0.033), while the levels of VEGF, MMP-9, Tsp-1, and EMMPRIN were unchanged.In vitro, the accumulation of the pro-angiogenic factors EMMRPIN, VEGF and MMP-9 in the supernatants was increased in the co-culture, while the accumulation of the anti-angiogenic factor Tsp-1 was decreased. When EMMPRIN was neutralized with a blocking antibody, supernatants derived from these co-cultures exhibited reduced migration, proliferation, and tube-like structure formation in functional assays.Conclusion:Our findings suggest an important role for EMMPRIN in mediating pro-angiogenic signals in RA patients, with EMMPRIN/Tsp-1 ratio serving as a marker of angiogenesis in RA. When administered to RA patients, TCZ in turn, exerts an anti-angiogenic effect through its regulation of EMMRPIN/CD147 levels.Disclosure of Interests:None declared

Autoinflammatory diseases are characterized by recurrent episodes of fever and localized or systemic inflammation and are caused by monogenic defects of innate immunity. The skin is commonly involved with various manifestations including erysipelas like rash and urticaria. Although vasculitis has been described in many autoinflammatory diseases, it has not been recognized as a characteristic feature of these diseases and autoinflammatory diseases are not listed as an etiology for vasculitis associated with a systemic disease in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. We describe herein 3 patients with different autoinflammatory diseases in whom leukocytoclastic vasculitis was one of the major and presenting symptoms. A review of the vast evidence in the literature for vasculitis in the spectrum of autoinflammatory diseases and a suggested pathophysiology is presented. We suggest the term autoinflammatory associated vasculitis to describe vasculitis associated with autoinflammatory diseases. Autoinflammatory diseases should be considered within the differential diagnosis of vasculitis.

The purpose of this study was to review the data on the etiology, risk factors, clinical presentations, and diagnosis of acute sacroiliitis. A Pubmed search utilizing the indexing term "acute sacroiliitis" was conducted and the data pertinent to the aim of the review was extracted and organized in accordance with the preplanned structure of the manuscript. The diagnosis of acute sacroiliitis is often challenging because of both the relative rarity of this presentation and diverse character of acute sacroiliac pain, frequently mimicking other, more prevalent disorders. Technetium bone scintigraphy can localize the disease process to the sacroiliac joint, while computed tomography or magnetic resonance imaging can be used for the detailed characterization and the extent of the disease as well as the diagnosis of complications. Pyogenic sacroiliitis is by far the most common cause of acute sacroiliitis. Brucellosis, acute sacroiliitis in the course of reactive arthritis, and crystalline-induced sacroiliitis frequently imitate pyogenic sacroiliitis. Acute sacroiliitis can rarely be also related to hematological malignancies or treatment with isotretinoin. Awareness to the possibility of acute sacroiliitis and a thorough physical examination are the necessary prerequisites to its timely diagnosis, while the appropriate laboratory and imaging studies should confirm the precise diagnosis and direct the appropriate treatment strategy.

We appreciate the interest of Akiyama et al in our report and thank them for the data presented in their letter.1 2 Akiyama et al have presented a thorough literature review and have described a positive and efficacious effect of tocilizumab in 11 cases of refractory polyarteritis nodosa (PAN) described in 6 case series. Indeed, the use of tocilizumab, an interleukin (IL)-6 inhibitor, in vasculitis is gaining evidence in the literature, specifically in large vessel vasculitis including giant cell arteritis and Takayasu arteritis.3 4 Nevertheless, it should be noted that although the …

Background:Elevated serum levels of interleukin (IL)-22 were reported in patients with ankylosing spondylitis (AS).[1]IL-22 was also reported to drive the osteogenic differentiation of mesenchymal stem cells.[2]Objectives:To confirm the fact that serum levels of IL-22 are elevated in AS patients and to examine the relationship between concentrations of IL-22 and degree of radiographic progression in AS patients.Methods:Seventeen male patients with established AS of more than 4 years duration signed the informed consent and donated 10 ml of peripheral blood. Demographic data was collected from patient’s charts. Disease activity indices were calculated for all patients and radiographic disease progression was calculated as mSASS. A control group included 6 healthy persons and 4 patients with advanced diffuse idiopathic skeletal hyperostosis (DISH). Serum levels of IL-22 were tested using enzyme-linked immunosorbent assay. Intergroup differences were examined using the Mann-Whitney test, while correlations were calculated using Pearson correlation coefficient.Results:Serum IL-22 levels were remarkably elevated in patients with AS, comparing to healthy individuals and patients with DISH (p=0.005). However, increased concentrations of IL-22 did not correlate with the degree of radiographic progression or AS disease activity indices, nor with disease duration or patient’s age. Presence of diarrhea, psoriasis, uveitis, or elevated levels of C-reactive protein did not influence the levels of IL-22 as well. More AS patients with elevated serum IL-22 were smokers (p=0.05).Fig. 1.Serum levels of interleukin 22 (pg/ml)Conclusion:The serum levels of IL-22 are elevated in patients with AS. It seems that smoking can be related to the elevated levels of serum IL-22 in AS. The significance of this data is unclear and further research is needed.References:[1]Zhang L, Li Y gang, Li Y hua, Qi L, Liu X guang, Yuan C zhong, et al. Increased frequencies of th22 cells as well as th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One. 2012;7(4).[2]El-Zayadi AA, Jones E, Churchman S, Baboolal T, Cuthbert R, El-Jawhari J, et al. Interleukin-22 drives the proliferation, migration and osteogenic differentiation of mesenchymal stem cells: a novel cytokine that could contribute to new bone formation in spondyloarthropathies. Rheumatology. 2016 Dec 10;56.Disclosure of Interests:None declared

Polyarteritis nodosa (PAN) is a necrotizing vasculitis predominantly affecting medium and small size arteries. Cyclophosphamide, a drug with narrow therapeutic range and poor safety profile, constitutes the treatment of choice for PAN vasculitis with major organ involvement. To describe our clinical experience in treating refractory PAN with infliximab (a TNF inhibitor), a drug with good tolerability and better safety profile than cyclophosphamide. Twenty-six PAN patients were admitted to our rheumatology unit between 2006 and 2017, of whom nine patients, with severe and refractory disease, were treated with infliximab after failure of standard treatment. We describe herein the patients’ characteristics, clinical manifestations, severity and response to infliximab treatment and review the current literature. Complete remission was defined as the absence of features of active disease and withdrawal of prednisone therapy. Significant improvement was defined as clinical improvement and prednisone dose reduction of at least 50% or a 50% reduction in immune modulatory medications other than prednisone. After 4 months of treatment, 8/9 (89%) patients achieved significant improvement, with two of them achieving complete remission. We suggest that anti-TNF agents, and in particular infliximab, are relatively safe and efficacious treatment options in refractory PAN. A randomized controlled trial should be done in order to objectively evaluate infliximab in PAN.

The interaction of dendritic cells (DCs) with the human microbiome, with distorted handling of the microbiota or its products via the direct effect of HLA B27, probably represents the initial element in the chain of events leading to the development of clinical axial spondyloarthritis. The mechanism of disease extension onto the skeleton and other tissues involved, such as uvea, may also involve migratory DCs. Finally, the role of DCs in the initiation of the inflammatory tissue response with activation of the IL-17 axis has been demonstrated. Further, some initial data suggests the possible connection of DCs with disease-related new bone formation.

The objective of this study is to review the data on entheseal involvement in systemic disorders. A Pubmed search utilizing the indexing terms "enthesis" and "enthesitis" was conducted and the data pertinent to the aim of the review was extracted and organized in accordance with the preplanned structure of the manuscript. A number of cadaver-based studies, as well as studies using ultrasonography and magnetic resonance imaging, have detailed new distinct aspects of enthesis physiology and pathology in a variety of rheumatic and non-rheumatic systemic disorders. Major progress has been done in characterization of separate components of the enthesis organ, imaging of entheses, elaboration of the role and features of entheseal disease in spondyloarthropathies, juvenile idiopathic arthritis, osteoarthritis, familial Mediterranean fever, hyperuricemia, and other systemic conditions. The knowledge acquired and summarized herein shows that entheses can be affected in various ways in variety of medical disorders with different pathogenesis. Better understanding of the risk factors, mechanisms and natural history of enthesopathies is warranted. The current progress in the understanding of entheseal involvement in systemic disorders represents just the first step in resolving the entheses-related enigmas.

Tofacitinib is a novel inhibitor of Janus kinase (JAK) 3 and JAK1 is recently introduced as treatment for rheumatoid arthritis.1 The JAK inhibitors are at the focus of research in a myriad of other inflammatory diseases2 ,3 as the JAK-(signal transducer and activator of transcription) STAT pathway has a central role in cytokine signal transduction. We herein describe a case of refractory polyarteritis nodosa (PAN) successfully treated with tofacitinib. A 28-year-old man had been diagnosed with PAN at age 14. He presented with livedo reticularis, arthritis and skin nodules with arteritis/fibrinoid necrosis confirmed on biopsy. Immunological panel at the time of diagnosis was negative for antineutrophil cytoplasmic antibodies, anti-nuclear antibodies, anti-Ro/SS-A antibodies, anti-La/SS-B antibodies, rheumatoid factor, with normal complement levels. He was treated with azathioprine and methotrexate for several years with drug-controlled complete remission. At age 24, his disease flared and he began to suffer from necrotic lesions of the scrotum and calves, excruciating abdominal pain and polyarthritis, with high C-reactive protein (CRP) levels (160–300 mg/L) for which he received recurrent intravenous methylprednisolone pulses and oral …

Background Approach to the diagnosis of axial spondyloarthrithis (axSpA) has changed in the last decade, with the aim of diagnosing the disease in its early form. Objectives The objective of this study was to explore change in the diagnostic pattern of axSpA in Northern Israel over the last 15 years. Methods Patients with the clinical diagnosis of axSpA from six rheumatology practices affiliated with the Rheumatology Unit of the Bnai Zion Medical Center in Haifa, Israel were recruited to the study. Ankylosing Spondylitis (AS) was diagnosed in the presence of sacroiliitis grade 2 or more on X-ray films; all other patients were considered as having non-radiographic axSpA. All patients were subdivided by time periods to 5 groups, and percentages of patients diagnosed in the non-radiographic stage of the disease, as well as patient demographic data were compared using exact Fisher test. Results One hundred twenty five patients were subdivided to 5 groups by periods of diagnoses (before 2000, 2001–2004, 2005–2008, 2009–2012, 2013–2016). Gradual increase in a proportion of patients diagnosed with non-radiographic axSpA was observed over years, with statistical significance achieved in 2013–2016 (p Conclusions Progressive increase in the proportion of patients diagnosed with non-radiographic form of axSpA over years was observed in this study. This finding, made on the basis of real life data, reflects change in the diagnostic approach to spondyloarthritis during the last decades. Disclosure of Interest None declared

Rituximab is a monoclonal antibody directed against the CD20 antigen on the surface of normal and malignant B lymphocytes. Its use in autoimmune conditions is rapidly expanding. Late-onset neutropenia (LON) is a well-recognized side effect of rituximab therapy in lymphoma patients. Only a small number of cases of LON have been reported in patients with autoimmune disorders. The aim of this work is to review cases in Israel and to compare them to published cases in the literature thus adding to the body of knowledge regarding this unusual phenomenon. Members of the Israeli Rheumatology Association were encountered by e-mail, requesting reports of cases of LON after therapy with rituximab. Submitted cases were reviewed, with demographics and clinical data collated and tabled. Current cases were compared to previously published rheumatology cases. Twelve episodes of LON following rituximab therapy were reported. All patients were female with an average age of 50 years (range 22-78). LON occurred at an average of 155 days after therapy (range 71-330). The average leukocyte count was 1,456 white cells, with an average of 413 neutrophils (range 0-1,170 neutrophils). Three of the patients underwent bone marrow biopsies which showed white cell line maturation arrest with an increased number of lymphocytes. No blasts were seen. Our results add support to the growing evidence that this adverse event usually follows a benign course and is not an absolute contraindication for repeat treatment if required in the future. However, vigilance is recommended with routine periodic blood counts, especially 5 months following rituximab administration when the risk is expected to be the highest.

Objective Fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc). Levels of lysyl oxidase (LOX), an extracellular enzyme that stabilizes collagen fibrils, have been found to be elevated in the skin of SSc patients, but have not been evaluated in the serum or correlated with the clinical parameters. We undertook this study to evaluate serum LOX levels in SSc patients and to correlate these levels with clinical parameters of SSc. Methods SSc patients were evaluated for demographic features, clinical manifestations, routine laboratory tests, serum autoantibodies, serum LOX concentrations, and nailfold capillaroscopy patterns. They underwent pulmonary function testing, echocardiography, and high-resolution computed tomography scans of the lung, assessment of skin fibrosis by the modified Rodnan skin thickness score (MRSS), and assessment of disease severity and activity by the Medsger severity scale and the Valentini activity index. Results Twenty-six SSc patients were evaluated and compared with 25 healthy controls and with 9 disease control patients with primary myelofibrosis. Almost 62% of the SSc patients (16 of 26) had limited cutaneous SSc (lcSSc), while 38% had diffuse cutaneous SSc (dcSSc) (10 of 26); 31% of the patients (8 of 26) had lung involvement. The LOX concentration in SSc patients was higher than that in healthy controls and similar to that in disease controls (P < 0.0001), and it was significantly higher in patients with dcSSc than in those with lcSSc (P = 0.006). The LOX concentration correlated with the MRSS in patients without lung fibrosis. Conclusion This study is the first to demonstrate high serum LOX levels in SSc patients that correlate specifically with skin fibrosis. These correlations suggest that LOX levels may serve as a novel biomarker of fibrosis. Future studies are warranted to determine whether LOX is a potential therapeutic target in SSc.

Objective.To describe the Israeli experience of treating adult-onset Still’s disease (AOSD) with tocilizumab (TCZ).Methods.Israeli rheumatologists who treated AOSD with TCZ filled in questionnaires on symptoms, number of tender and swollen joints, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and dosage of prednisone at initial TCZ administration, after 6 months, and at the end of followup.Results.Nine male and 6 female patients, aged 33 ± 12 years, mean disease duration 9 years (range: 1–25) were identified. They had used a mean of 3.6 disease-modifying drugs, including 10 patients with tumor necrosis factor blockers. Intravenous TCZ 8 mg/kg was administered every 4 weeks (12 patients) or every 2 weeks (3 patients). All patients completed at least 6 months of treatment. The mean followup period was 15.7 ± 9 months. At the onset of therapy, despite the use of prednisone (27.6 ± 26.3 mg/d), all patients reported joint pain. Fever was reported in 9 patients, rash in 7, pleuritis in 3, and hepatitis in 2 before TCZ use, with mean ESR and CRP levels of 60 ± 28 mm/h and 11.6 ± 15 mg/dl, respectively. After 6 months of treatment and at the end of followup, the number of tender and swollen joints, the ESR and CRP levels, and the prednisone dosage decreased significantly. Only 2 patients still complained of mild arthralgias, and none reported systemic symptoms at the end of followup.Conclusion.TCZ 8 mg/kg was extremely efficacious in treating adult patients with refractory Still’s disease. Both TCZ and interleukin 1 blockade should be considered in the treatment algorithm of AOSD. Randomized controlled studies are needed to validate these findings.

Anti-tumor necrosis factor (TNF) agents have become central players in the management of autoimmune and rheumatic disease. With the wide use of anti-TNF agents today, we have become aware of rare autoimmune complications as systemic lupus erythematosus and psoriasis, yet rarely has large vessels vasculitis been described. We herein describe a case of cytoplasmic anti-neutrophil cytoplasmic antibody (c-ANCA) (with myeloperoxidase (MPO) antibodies)-associated large vessel vasculitis (aortitis) that developed during anti-TNF treatment for ankylosing spondylitis. Awareness of this rare, but serious, adverse event of these commonly used agents in rheumatic diseases is of importance.

Objective.To assess the association between treatment with anti-tumor necrosis factor-α (TNF-α) agents and the occurrence of hospitalizations, their causes and complications, compared to treatment with traditional disease-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS).Methods.A retrospective cohort study was conducted of patients with RA, AS, and PsA treated with anti-TNF-α agents between April 2002 and December 2007. Patients were assessed during the period of anti-TNF-α treatment (Group B) and compared to an equivalent period before initiation of anti-TNF-α therapy (Group A). All hospitalization charts were reviewed and diagnoses, comorbidities, concomitant medications, and clinical course were analyzed. Statistical analysis was performed using multivariate mixed Poisson regression.Results.In the study period of 57 months, 735 hospitalization events of 327 patients were analyzed. Statistically significant decreases were seen in the total number of hospitalization events as well as hospitalizations due to exacerbation of rheumatic diseases in Group B compared to Group A (44.4 vs 74.2 and 21.9 vs 47.5 per 100 patient-years, respectively; p < 0.0001). More infectious events (7.4 in Group B compared to 4.6 per 100 patient-years in Group A; p = 0.043) were associated with anti-TNF-α treatment, older age, and underlying disease, because patients with RA had higher rates of infections compared to patients with PsA and patients with AS.Conclusion.The overall effect of anti-TNF-α therapy was a significant decline in total hospitalization events. The decrease was more prominent in patients with RA than in patients with AS and patients with PsA, and reflected the significant decrease in hospitalizations due to rheumatic disease exacerbation. The decrease was more pronounced than the observed increase in infectious events.

In the past decade, tocilizumab, an anti interleukin-6 agent, has been successfully developed as a therapeutic agent for the treatment of rheumatoid arthritis and systemic onset juvenile idiopathic arthritis. In addition to countering inflammation, tocilizumab is also known affect B cell as well as T cell function, thus modulating immune function, and impact osteoclasts, as well as vascular endothelial growth factor. As such, its efficacy is currently being explored in a large number of autoiommune conditions including a number of vasculitides, systemic lupus erythematosus, systemic sclerosis, polymyositis, graft versus host disease, relapsing polychondritis, as well as Behcet's syndrome, spondyloarthropathies, and tumor necrosis factor receptor associated periodic syndrome.

Disease patterns and manifestations may vary among different populations and change over time. The purpose of our study was to define the demographic, clinical, roentgenologic, and laboratory findings in a recent cohort of psoriatic arthritis patients followed up in rheumatology clinics in northern Israel. We conducted a cross-sectional study of 149 psoriatic arthritis patients. Demographic, clinical, laboratory, and radiological data, with emphasis on the pattern of arthritis, treatment regimens, and co-morbidities were obtained from patient interviews and rheumatology file reviews. The mean age of our patients was 58.2, with a female preponderance (57.3%). Skin involvement preceded the arthritis or was diagnosed simultaneously in 90.1% of cases. The most common joint involvement was an RA-like arthritis (49.7% of the patients) correlating positively with age, female gender, and disease duration. Dactylitis and nail involvement were observed in 33.6 and 36.2% of the patients, respectively. Radiographic bone erosions were noted in a third of the patients, correlating with DIP and RA-like arthritis patterns. Most patients were treated with methotrexate (73.8%) and a combination therapy (41.4%). An increased incidence of hypertension, hyperlipidemia, and diabetes mellitus was noted in our cohort compared to the general Israeli population. Our survey, the first of its kind conducted in Israel, noted a relative increase in the polyarticular manifestation of PsA and a decrease in spondyloarthropathy, compared to historic series, with more aggressive disease found in women above the age of sixty. These findings are in line with recent surveys.

Pamidronate, along with other bisphosphonates, has been used for treatment of bone pain secondary to malignant involvement or metastatic disease for years. Some data, however, have also accumulated on the utility of pamidronate in a variety of benign conditions frequently handled by rheumatologists. This study aims to review the available published data regarding the potential use of pamidronate in rheumatology practice. Methods include the review of relevant articles retrieved by a PUBMED search utilizing the index term "pamidronate". All available randomized control trials, open trials, and case series, as well as properly reported case studies evaluating usage of pamidronate in rheumatic disorders, have been included in the literature review. The efficacy of pamidronate in patients with spondyloarthropathies; synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome; hypertrophic osteoarthropathy; osteoporotic vertebral fractures; chronic back pain due to disk disease or spinal stenosis; Charcot arthropathy; transient osteoporosis; and complex regional pain syndrome-I, has been demonstrated in more than 40 reports, the majority of which, however, were not controlled studies. In some of reviewed conditions, aside from providing analgesic relief, pamidronate may also have disease-modifying properties. While used in different doses in a variety of rheumatic disorders, pamidronate was generally reported to be well tolerated with an overall good safety profile. Pamidronate may represent an effective and safe choice for a spectrum of rheumatic patients, suffering from intractable musculoskeletal pain, unresponsive to traditionally recommended therapies. Large randomized, controlled studies examining the efficacy of pamidronate in the rheumatic conditions are urgently needed.

Our aim was to investigate a possible association between patterns of anti-dsDNA antibody isotypes (IgG, IgM, and IgA), rheumatoid factor (RF) isotypes (IgG, IgM, IgA), and IgG anti-C reactive protein (CRP) and systemic lupus erythematosus (SLE) disease activity (SLEDAI).Our study group included 98 patients, 86 women and 12 men, with a mean SLEDAI score of 7.9 +/- 4.1. We divided the patients into 4 groups by the serum anti-dsDNA antibody isotype intensity level.We found that patients in group 1 (IgGIgM, 42 patients) had a statistically significantly higher SLEDAI score than group 2 (IgGIgM, 13 patients) (10.57 +/- 4.62 versus 5.6 +/- 4, P = 0.0012), group 3 (IgG = IgM, 8 patients) (10.57 +/- 4.62 versus 6.2 +/- 1.98, P = 0.04), and group 4 (none, 35 patients) (10.57 +/- 4.62 versus 6 +/- 1.5, P = 0.0001). SLE patients with IgG RF or IgM RF isotype present had a significantly higher SLEDAI score compared with those without IgG RF or IgM RF (10.57 +/- 4.8 versus 7.6 +/- 4.1, P = 0.03, 10.6 +/- 5 versus 7.6 +/- 3.9, P = 0.046). The presence of IgA RF isotype was not associated with a higher SLEDAI score. IgG anti-CRP did not correlate differentially with SLEDAI scores.A combination of high-titer IgG anti-dsDNA with a positive RF of IgM isotype may serve as a marker for more active SLE.

To examine recent data about the association between rheumatic disorders and cancer. This article focuses on paraneoplastic rheumatic disorders, which usually precede by a short period of time the diagnosis of malignancy, and on malignant transformation, which occurs late in the course of rheumatic disorders. Evidence of causality between malignancies and rheumatic disorders was reviewed based on statistical indicators (standardized incidence ratios and odds ratios) and by applying Bradford Hill's criteria of causality.Firm epidemiological evidence was found attesting that dermatomyositis and polymyostis may present as paraneoplastic syndromes. Several other musculoskeletal disorders may be present akin to paraneoplastic syndrome, based on clinicians' impressions, but with scarce epidemiological evidence supporting a causal determinism. In contrast, robust evidence has accumulated on the role of longstanding rheumatoid arthritis, Sjögren's syndrome and systemic sclerosis as premalignant conditions. Evidence that systemic lupus erythematosus may evolve into lymphoma is equivocal.The link between malignancies and rheumatic disorders may impact on clinical practice. First, paraneoplastic rheumatic syndromes can provide the clinician with hints for earlier diagnosis of occult cancer. Second, the risk of malignant transformation during the course of rheumatic disorders may motivate the search for strategies aimed at prevention.

Background The concept of “enthesis organ” allows a new look at the nature of enthesis involvement in some rheumatic and nonrheumatic systemic disorders. Objectives To describe the various presentations of enthesopathy in the course of systemic medical disorders using the available literature data. Methods Review of relevant articles from 1996 to 2006 retrieved by a Medline search utilizing the index terms “enthesis,” “enthesitis,” and “tendonitis.” The list of articles reviewed herein is not exhaustive, with preference given, where possible, to studies and surveys over case reports as well as the most recent literature reflecting new developments on the subject. Results Enthesis is defined as the site of insertion of a tendon, ligament, fascia, or articular capsule into bone. Pain originating in the free nerve endings enriched entheses (enthesalgia) may represent a potential cause of chronic musculoskeletal pain in some individuals. Enthesis involvement in the disease process is well appreciated in spondyloarthropathies and in rheumatoid arthritis, though overshadowed by synovitis in the latter. Calcium deposition diseases may constitute the most significant articular cause of enthesopathies in the general population. New data may shed light on the possible pathophysiologic role of enthesopathy in the development of osteoarthritis. Various metabolic and endocrine conditions may manifest with enthesopathy features. The pathogenic mechanisms of enthesis involvement are not uniform and differ in the diverse disorders. Conclusions The concept of enthesopathy as a variety of syndromes in the course of many rheumatic, metabolic, and endocrine disorders should be appreciated. Exercise of a high level of suspicion toward enthesopathic involvement, and greater knowledge of enthesopathy’s characteristic patterns and diagnostic possibilities, may allow better management of many patients in rheumatology practice.

Semaphorin 3A (sema3A) plays a regulatory role in immune responses, mainly affecting the activation of regulatory T cells. It has been found to correlate with disease activity in rheumatoid arthritis and systemic lupus erythematosus (SLE). To investigate the expression of sema3A in patients with systemic sclerosis (SSc) compared to healthy controls and SLE disease controls and to correlate it with clinical characteristics, 27 SSc patients, 42 SLE patients and 28 healthy controls were enrolled. Serum level of sema3A was measured by ELISA, and expression of sema3A on regulatory T cells was evaluated by FACS analysis. SSc patients were evaluated for demographics, clinical manifestations, routine laboratory results, nailfold videocapillaroscopy, pulmonary function tests, echocardiograms, modified Rodnan skin score, and disease activity and severity scores. Serum levels of semaphorin 3A were lower in SSc compared to healthy controls 14.38 ± 5.7 versus 27.14 ± 8.4 ng/ml, p < 0.0001 and similar to SLE 15.7 ± 4.3 ng/ml. The expression of semaphorin 3A on regulatory T cells was also lower in SSc compared to healthy controls 61.7 ± 15.7 versus 88.7 ± 3. 7 % (p < 0.0001). Semaphorin 3A serum level inversely correlated with the duration of disease: r = −0.4, p = 0.036 and with low C4 level r = 0.66, p = 0.026. SCL-70 antibody positivity was associated with a lower semaphorin 3A level (difference in mean of 3.44, p = 0.06). Sema3A expression is low in SSc serum and more specifically on regulatory T cells. This may help explain the reduced activation of regulatory T cells in SSc.

Behcet's disease (BD) has a higher prevalence in countries along the ancient silk route, but the actual prevalence in Israel is unknown. We evaluated the occurrence and clinical expression of BD in the northern region of Israel: in the whole population and by ethnic groups. The sample included all adult patients with BD (International Study Group criteria) treated at three medical centers in northern Israel. Patient data were collected by file review and physician survey. Relevant demographic data for the population served by the medical centers were obtained from the official Israeli authorities. A total of 112 patients were identified. The overall prevalence of BD was 15.2/100,000 and was similar in men and women. The prevalence rates among the Jewish, Arab, and Druze populations were 8.6, 26.2, and 146.4 per 100,000, respectively. Age at disease onset was similar in all ethnic groups and significantly lower in males (28.6+/-9.7 vs 32.9+/-11.3, p=0.03). There were no differences in disease manifestations by sex or ethnicity. All Druze patients were HLA-B5 positive, compared to 80.8% of the Arab patients and 72.0% of the Jewish patients. Recurrent oral ulcers in family members were more common in Arab patients (p=0.004). The BD severity index was significantly lower in Druze patients (p=0.05), mainly in males (p=0.03). This study confirms the high prevalence of BD in Israel and the variability in disease rates and expression by ethnic origin. Our findings, particularly regarding the Druze population, call for further field surveys and genetic studies.

Objective To present the data available supporting the existence of an arthropathy associated with hepatitis C infection. Methods The MEDLINE database was searched for “arthritis” intersecting with “hepatitis C” in addition to the authors’ investigations and experience on this subject. Results Arthritis, not otherwise explained, has been noted in 2% to 20% of hepatitis C virus (HCV) patients. This arthritis is rheumatoid-like in two thirds of the cases and a waxing/waning oligoarthritis in the rest. Cryoglobulinemia alone does not explain the arthritis, and there is difficulty in differentiating it from rheumatoid arthritis. The arthropathy is nonerosive/nondeforming. Whereas nonsteroidal anti-inflammatory drugs, low-dose corticosteroids, and hydroxychloroquine may be helpful, conventional treatment of arthritis may be problematic in the context of viral hepatitic arthropathy. Antiviral therapy is most effective, even without viral clearance, but rheumatic complications may ensue. Conclusions HCV arthropathy should be considered in the differential diagnosis of new-onset arthritis.

The benefit of combining quinacrine (Qn) with hydroxychloroquine (HCQ) in the treatment of systemic lupus erythematosus (SLE) was previously re-evaluated by us. In our current study we observed that, in 11 active SLE patients (SLEDAI score 5 - 12), the addition of Qn (100 mg=day) to their existing ongoing therapeutic regimens resulted in a significant attenuation of their previously persistent anticardiolipin antibody (aCL) response. This was in comparison with a matched non-Qn treated control group composed of 14 randomly chosen aCL-positive SLE patients with a similar SLEDAI score 6 - 10. Prior to Qn treatment the therapeutic regimens of 12 months’ duration, included in all cases HCQ (400 mg=day), in many cases prednisone (P, 10 - 20 mg=day) and in some additional cases immunosuppressive drugs. SLEDAI scores and aCL levels were monitored during the entire follow-up period which totaled 24 months in the study group and 15 - 18 months in the controls. Along with the beneficial effect of the added Qn on SLEDAI scores, aCL disappearance was documented in eight of 11 patients and remained negative during 8 - 12 months of follow-up (P = 0.004), compared with such a change in only three of 14 non-Qn treated aCL-positive patients (P = 0.18). We conclude that the added Qn treatment to former established therapeutic protocols may eliminate aCL response in SLE patients. Whether this agent’s effect is permanent needs further elucidation.

Aortitis, which is well described in patients with other spondyloarthritides, has been rarely cited in relation to psoriatic arthropathy (PsA). Two patients with known PsA, who developed aortitis, are reported herein. The PubMed database was searched using the following keywords: aortitis, Takaysu arteritis, PsA, ankylosing spondylitis, reactive arthritis, inflammatory bowel disease. The relevant articles were critically reviewed and pertinent data organized. Analysis of 5 cases of aortitis in patients with PsA, including the 2 cases reported herein, revealed no specific pattern of PsA joint involvement in the patients who developed aortitis. All aortic segments can be involved and complications, such as insufficiency of the aortic valve and stenosis of the major aortic branches, have been described. The genetic association involving the IL12B locus may be involved in the clinical association of aortitis and spondyloarthritis.

To evaluate the cardiovascular response to postural challenge in patients with chronic fatigue syndrome (CFS) and to determine whether the degree of instability of the cardiovascular response may aid in diagnosing CFS.Patients with CFS (n = 25) and their age- and gender-matched healthy controls (n = 37), patients with fibromyalgia (n = 30), generalized anxiety disorder (n = 15), and essential hypertension (n = 20) were evaluated with the aid of a standardized tilt test. The blood pressure (BP) and heart rate (HR) were recorded during 10 minutes of recumbence and 30 minutes of head-up tilt. We designated BP changes as the differences between successive BP values and the last recumbent BP. The average and standard deviation (SD) were calculated. Time curves of BP differences were loaded into a computerized image analyzer, and their outline ratios and fractal dimensions were measured. HR changes were determined similarly. The average and SD of the parameters were calculated, and intergroup comparisons were performed.On multivariate analysis, the independent predictors of CFS patients versus healthy controls were the fractal dimension of absolute values of the systolic BP changes (SYST-FD.abs), the standard deviation of the current values of the systolic BP changes (SYST-SD.cur), and the standard deviation of the current values of the heart rate changes (HR-SD.cur). The following equation was deduced to calculate the hemodynamic instability score (HIS) in the individual patient: HIS = 64.3303 + (SYST-FD.abs x -68.0135) + (SYST-SD.cur x 111.3726) + (HR-SD.cur x 60.4164). The best cutoff differentiating CFS from the healthy controls was -0.98. HIS values-0.98 were associated with CFS (sensitivity 97%, specificity 97%). The HIS differed significantly between CFS and other groups (P.0001) except for generalized anxiety disorder. Group averages (SD) of HIS were CFS = +3.72 (5.02), healthy = -4.62 (2.26), fibromyalgia = -3.27 (2.63), hypertension = -5.53 (2.24), and generalized anxiety disorder = +1.08 (5.2).The HIS adds objective criteria confirming the diagnosis of CFS.

Etanercept is a fusion protein that consists of extracellular ligand binding domain of the tumor necrosis factor alpha (TNF) receptor (p75) coupled with the Fc portion of human IgG. It binds TNF-α, thus blocking its interaction with TNF-α receptor. TNF-α is a proinflammatory cytokine that has a pivotal role in the inflammatory response in rheumatoid arthritis (RA). It also induces chemokine production and upregulates adhesion molecules. Indeed, etanercept is a mainstay therapy in RA [1]. Several pulmonary adverse reactions have been reported in patients treated with etanercept, the most important of which is tuberculosis. Other pulmonary complications include: granulomatous reaction, namely sarcoidosis (26 cases in the literature) [1–3], lung rheumatoid nodules [4], drug induced lupus related pleural effusion [5], and pulmonary lymphohistiocytic reactions [6]. In this report, we describe a case of severe RA pseudoempyematous pleural effusion that appeared with etanercept therapy and resolved promptly after its discontinuation.

mg/day diacerein (50 mg twice daily) was significantly superior (P < 0.05) to placebo using the primary criterion (visual analog scale [VAS] assessment of pain on movement). Significant improvement (P < 0.05) was also observed for the secondary criteria, which included the Western Ontario and McMaster Universities OA Index (WOMAC), the WOMAC subscores, and the VAS assessment of handicap. In patients treated with diacerein dosages of 50 mg/day and 150 mg/day, favorable but not significant results were observed for the primary criterion. The best daily dosage of diacerein, calculated from the effect on the VAS assessment of pain on movement, was 90.1 mg. In the per-protocol population, the analysis of the primary criterion showed significant dose-dependent differences (P < 0.05) between each of the 3 diacerein dosages and the placebo. No differences were observed among the 3 diacerein groups. A significantly higher incidence (P < 0.05) of adverse events (AEs), as well as a higher rate of dropoout due to AEs, was observed in patients treated with 150 mg/day diacerein versus those treated with placebo, 50 mg/day diacerein, or 100 mg/day diacerein. Mild-to-moderate transient changes in bowel habits were the most frequent AEs, increasing with the dosage. Conclusion. Diacerein, a drug for the treatment of OA, was shown to be an effective treatment for symptoms in patients with knee OA. Taking into account both efficacy and safety, the optimal daily dosage of diacerein for patients with knee OA is 100 mg/day (50 mg twice daily).

To compare the hemodynamic and ventilatory responses to autonomic challenge evoked by upright tilt table testing in patients with chronic fatigue syndrome (CFS) to healthy individuals.Thirty-two consecutive patients with CFS and 32 healthy volunteers were evaluated with the aid of the recently introduced capnography head-up tilt test (CHUTT). The main outcome measures were values of blood pressure (BP), heart rate (HR), respiratory rate (RR), and end-tidal pressure of co2 (ETPco2) recorded during recumbence and tilt. In addition, the end points of vasodepressor and cardioinhibitory reactions, hyperventilation (defined by ETPco225 mm Hg) and the postural tachycardia syndrome, were recorded.The BP, HR, RR, and ETPco2 recorded during recumbence were similar in both groups. During tilt, patients with CFS developed significantly lower systolic BP, diastolic BP, and ETPco2, and a significant rise in HR and RR (P.01). In CFS patients, the postural tachycardia syndrome occurred in 44%, vasodepressor reaction in 41%, cardioinhibitory reaction in 13%, and hyperventilation in 31% of cases. One or more end points of the CHUTT were reached in 78% of patients with CFS but in none of the controls (P.0001).In most patients with CFS, a spectrum of abnormal homeostatic reactions is diagnosed with the aid of the CHUTT. Data provided by the CHUTT may reinforce the clinical diagnosis by adding objective and unbiased criteria to the subjective assessment of CFS.

Background: Although the benefit of antimalarials in the treatment of cutaneous LE is well established, the effect of combined hydroxychloroquine and quinacrine treatment in systemic lupus erythematosus with major organ involvement remains underappreciated.Patients: Six active SLE patients (SLEDAI score > 5 points), with a mean duration of illness 9.1 yr (range 2 ± 17 yr) were started on quinacrine (100 mg/d) following failure to achieve clinical remission on a therapeutic regimen which included a maintenance dose of hydroxychloroquine (400 mg/d) together with prednisone (either 10 ± 20 mg/d or higher daily doses of this agent for short periods) and azathioprine (150 mg/d) or methotrexate (7.5 mg/week).Outcome: In 5=6 of the patients the addition of quinacrine to the previous treatment resulted in complete remission (SLEDAI 0 ± 2 points), which persisted over the follow-up period [mean 2.2 yr (range 0.5 ± 3.5)]. During this period hydroxychloroquine and azathioprine were reduced to 200 mg/d and 100 mg/d respectively, whereas prednisone was modified as follows: in 2 patients daily administration was discontinued; in one the dose was reduced to 2.5 mg/d (from that of 20 mg/d); in 2 others the previous need for an intermittent course was avoided. However, in one out of the six patients the addition for 3 months of quinacrine to the therapeutic protocol did not result in clinical improvement and was therefore discontinued.Conclusions: The promising results of this preliminary investigation encourages the combined use of the two antimalarial drugs in appropriate candidates. This modality may induce remission, seems to be safe and possesses a steroid sparing effect.

Gout is rare among young women. The prevalence of gout is increasing in the western world and the Far East, probably owing to life style changes. The association between hyperuricemia and gout, the metabolic syndrome and atherosclerosis is stronger in women. 40 years ago, the increased prevalence of hyperuricemia and gout in Filipino men living in the United States was described. Recently, Filipino men and women living in the western world were found to have increased risk of the metabolic syndrome and atherosclerosis. We describe two unusual cases of gout in premenopausal Filipino women living in Israel, both of which suffered from hypertension. We also describe the current knowledge about gout in women, in general, and in migrant Asian women, in particular, with an emphasis on its relations to the metabolic syndrome and atherosclerosis. The occurrence of gout in relatively young migrant Filipino women might signal a change in the epidemiology of this disease, and might signal that these women are more prone to develop the metabolic syndrome and its complications.

Resume Les paralysies isolees du nerf hypoglosse (NH) ont ete decrites dans plusieurs pathologies impliquant le rachis cervical et/ou la base du crâne, cependant les paralysies unilaterales du NH secondaire a une polyarthrite rhumatoide (PR) ont rarement ete rapportees. Nous presentons une observation peu commune de paralysie isolee du NH suite a une atteinte cervicale rhumatoide caracterisee par la formation d’un pannus au niveau de l’articulation C1–C2 a l’origine d’une subluxation atloido-axoidienne, d’erosions du condyle occipital droit, des masses laterales et de l’arc anterieur de C1. Un traitement d’attaque par methylprednisolone suivi par un traitement d’entretien par prednisone a entraine une amelioration spectaculaire. Nous discutons egalement des modalites diagnostiques et du suivi.

Degenerative lumbar spinal stenosis, manifesting as chronic low back pain and neurogenic claudication, is an increasing chronic problem in an aging population, with limited effective conservative treatment options. Based on previous reports on the utility of subcutaneous calcitonin and two anectodal cases, we launched an open therapeutic trial of IV monthly pamidronate infusions, over a course of 3-6 months in this condition. Of 24 patients, 75% reported pain improvement, with the mean VAS score improved by 40%; while composite functional improvement in walking time, activities of daily living, and sense of well being was reported by 66%, with a mean improvement of 50%. The results of this pilot trial suggest the usefulness of this modality and warrant examination in a controlled clinical trial.

Objectives: Rheumatic disorders associated with cancer include a variety ofconditions, most of which have no features distinguishing them from idiopathic rheumatic disorders. It is generally held that an extensive search for occult malignancy in most rheumatic syndromes is not recommended unless accompanied by specific findings suggestive of malignancy. The objective of this review are to identify rheumatic syndromes associated with cancer, to call attention to features that may suggest the presence of a hidden cancer, and to examine the role to additional clinical and laboratory data as clues to the possible neoplastic cause of those syndromes. Methods: A MEDLINE search of the literature dealing with cancer-associated rheumatic syndromes was conducted. Results: Review of the literature identified significant progress in this area. First , the association of malignancy with certain rheumatic syndromes was convincingly established, such as asymmetric polyarthritis presenting in the elderly with an explosive onset, rheumatoid arthritis with monoclonal gammopathy, Sjogren's syndrome with monoclonality, hypertrophic osteoarthropathy, dermatomyositis, polymyalgia rheumatica with atypical features, Lambert-Eaton myasthenic syndrome, palmar fasciitis and arthritis, eosinophilic fasciitis poorly responsive to corticosteroid therapy, erythema nodosum lasting more than 6 months, and onset of Raynaud's phenomenon or cutaneous leukocytoclastic vasculitis after age 50 years. Second , the list of cancer-associated rheumatic syndromes was extended by including additional entities such as benign edematous polysynovitis, sacroiliitis, adult-onset Still's disease, dermatomyositis sine myositis, systemic sclerosis, Sweet's syndrome, osteomalacia, skeletal hyperostosis, antiphospholipid syndrome, and essential mixed cryoglobulinemia. Third , evidence was provided substantiating that certain longstanding rheumatic syndromes, in particular rheumatoid arthritis, Felty's syndrome, Sjogren's syndrome, dermatomyositis, systemic sclerosis, systemic lupus erythematosus, and temporal arteritis behave like "premalignant conditions." Fourth , it was shown that the recognized tumor markers alpha-fetoprotein, prostate-specific antigen, CA-125, CA 19-9, and CA-3 have low sensitivity and specificity in screening for occult cancer in a population of rheumatic patients, whereas the presence of a monoclonal gammopathy in rheumatoid arthritis and the monoclonal antibody 17-109 in Sjogren's syndrome are reliable signs of malignant transformation. Conclusions: The presence of specific rheumatic syndromes and certain clinical and laboratory findings may justify a workup for hidden cancer. Studies of the epidemiology of the cancer-associated rheumatic syndromes and evaluation of the validity of aforementioned clues in prospectives studies are goals for future investigations.