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Streptococcus is well associated with a myriad of inflammatory diseases. Among others, this bacterium is linked to the triggering of psoriasis and to post-streptococcal reactive arthritis (PSRA), an arthritis which is typically confined to peripheral joints. Three patients who developed acute psoriatic spondyloarthritis (SpA) following a recent streptococcal infection are described in this article. We searched the existing literature for cases of axial involvement in PSRA and reviewed the association between streptococcal infection and psoriasis or psoriatic arthritis )PsA). In all patients, psoriatic SpA occurred within 7-10 days of a confirmed streptococcal infection. The main presenting syndrome was inflammatory back pain with evidence of acute axial spondyloarthritis on magnetic resonance imaging. One patient had guttate psoriasis, the second patient developed pustular psoriasis, and the third patient had exacerbation of pustular palmoplantar psoriasis. Two patients required treatment with tumor necrosis factor alpha (TNF-α) blockers. Axial involvement in PSRA is very rare. A potential association of streptococcal infection and development of PsA has been explored in several articles. However, to the best of our knowledge, acute psoriatic SpA as a manifestation of PSRA has yet to be described. Acute psoriatic SpA should be considered in the differential diagnosis of new-onset inflammatory back pain followed by psoriasis in young adults who had a recent throat infection. KEY POINTS: • Our case series describes three cases of acute psoriatic spondyloarthritis that occurred within 7--10 days of a confirmed streptococcal infection and progressed to full blown chronic disease. • Acute psoriatic spondyloarthritis as a manifestation of post streptococcal reactive arthritis should be considered in the differential diagnosis of new onset inflammatory back pain followed by psoriasis in young adults who had a recent throat infection.

Background: Infectious diseases and vaccines can occasionally cause new-onset or flare of immune-mediated diseases (IMDs). The adjuvanticity of the available SARS-CoV-2 vaccines is based on either TLR-7/8 or TLR-9 agonism, which is distinct from previous vaccines and is a common pathogenic mechanism in IMDs. Methods: We evaluated IMD flares or new disease onset within 28-days of SARS-CoV-2 vaccination at five large tertiary centres in countries with early vaccination adoption, three in Israel, one in UK, and one in USA. We assessed the pattern of disease expression in terms of autoimmune, autoinflammatory, or mixed disease phenotype and organ system affected. We also evaluated outcomes. Findings: 27 cases included 17 flares and 10 new onset IMDs. 23/27 received the BNT - 162b2 vaccine, 2/27 the MRNA-1273 and 2/27 the ChAdOx1 vaccines. The mean age was 54.4 ± 19.2 years and 55% of cases were female. Among the 27 cases, 21 (78%) had at least one underlying autoimmune/rheumatic disease prior the vaccination. Among those patients with a flare or activation, four episodes occurred after receiving the second-dose and in one patient they occurred both after the first and the second-dose. In those patients with a new onset disease, two occurred after the second-dose and in one patient occurred both after the first (new onset) and second-dose (flare). For either dose, IMDs occurred on average 4 days later. Of the cases, 20/27 (75%) were mild to moderate in severity. Over 80% of cases had excellent resolution of inflammatory features, mostly with the use of corticosteroid therapy. Atypical rheumatic manifestations included idiopathic pericarditis (n = 2), neurosarcoidosis with small fiber neuropathy (n = 1), demyelination (n = 1), and myasthenia gravis (n = 2). In 22 cases (81.5%), the insurgence of Adverse event following immunization (AEFI)/IMD could not be explained based on the drug received by the patient. In 23 cases (85.2%), AEFI development could not be explained based on the underlying disease/co-morbidities. Only in one case (3.7%), the timing window of the insurgence of the side effect was considered not compatible with the time from vaccine to flare. Interpretation: Despite the high population exposure in the regions served by these centers, IMDs flares or onset temporally-associated with SARS-CoV-2 vaccination appear rare. Most are moderate in severity and responsive to therapy although some severe flares occurred. Funding: none.

Background Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. Materials and methods Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. Results Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P Conclusions This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA.

14-3-3η may represent a useful diagnostic biomarker for rheumatoid arthritis (RA). We assessed the prevalence and serum levels of 14-3-3η in patients with RA and in patients with other rheumatic diseases. Serum levels of 14-3-3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases, and in 66 healthy subjects. All of the sera samples were evaluated by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). Median (IQR) 14-3-3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075-3.11)] and in patients with established RA [0.15 ng/ml (0.08-1.26)] than in healthy subjects [0 ng/ml (0-0)] and disease controls: SLE [0.01 ng/ml (0-0.055)], AS [0.05 ng/ml (0-0.255)], and PsA [0.01 ng/ml (0-0.065)]. The prevalence of 14-3-3η positivity in patients with early RA was 58%, significantly higher than that in disease controls and healthy subjects (p 0.001). In patients with established RA, this prevalence was 43%, and it was significantly higher than that in patients with other rheumatic diseases and healthy subjects (p 0.05), excluding the AS group (p = 0.054). In the early RA cohort, the positivity for 14-3-3η, RF, and anti-CCP was 58%, 67%, and 71%, respectively. Eighty-two percent of the patients in this cohort were positive for at least one of these biomarkers. The concentration of 14-3-3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases.

We sought to evaluate a possible link between parvovirus B19 infection and the clinical and laboratory expression of systemic lupus erythematosus (SLE). SLE patients were examined to evaluate their clinical status and disease activity. A complete Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score was obtained for each patient. In addition, we determined the level of systemic involvement throughout the course of the disease. Blood levels of IgM and IgG antibodies to parvovirus B19, levels of anti-dsDNA, C3, and C4 were measured. A PCR real-time assay was used to determine the presence of parvovirus B19 genetic material. The viral genome was found in sera of 2 of 51(3.9%) patients with SLE. There was no correlation between viral serology and the clinical and serological parameters of the disease. More SLE patients with secondary antiphospholipid syndrome (APS) had IgG and IgM antibodies to the virus (p

Golimumab is a recombinant human monoclonal antibody targeted against tumour necrosis factor-alpha (TNF-α). Golimumab is effective in the management of patients with active psoriatic arthritis (PsA). The aim of this study is to evaluate the clinical efficacy and survival of golimumab monotherapy versus co-administration with methotrexate (MTX) in patients with PsA in the clinical practice. This retrospective observational trial included patients with PsA. Efficacy was assessed by disease activity scores – DAS28, BASDAI, physician global assessment of disease (PGA) and CRP. Golimumab survival rate was estimated using the Kaplan-Meier analysis and univariate and multivariate Cox regression models. Forty-one patients with PsA were recruited; 26 patients were treated with golimumab, whereas 15 patients received combination therapy with MTX. The treatment resulted in significantly improved clinical measures of disease activity in comparison with baseline, including DAS28 CRP (4.1 vs 2.6, p ≤ 0.0001) and BASDAI (5.6 vs 3.8, p ≤ 0.001). Overall, 29 (71%) patients continued golimumab treatment (18 patients on monotherapy and 11 on combination therapy). The difference in the duration of golimumab survival between the combination therapy and monotherapy groups was not statistically significant (12.5 vs 12 months, p = 0.2). Similar efficacy profiles and survival rates were documented in patients with PsA regardless of the co-administration of methotrexate.

Background Approximately 5% of idiopathic recurrent pericarditis (IRP) patients are refractory or intolerant to NSAIDs, Colchicine and corticosteroids. The empiric treatment approach for these patients includes immunosuppression with Azathioprine (AZA) or immunomodulation with intravenous human immunoglobulin (IVIG). We assessed the efficacy and safety of long-term Anakinra treatment in refractory IRP patients after failure of prior immunosuppressive therapy and/or failure of IVIG. Methods Clinical data of seven IRP patients were retrospectively analyzed. Treatment efficacy was determined by decrease of IRP recurrence and by the ability to withdraw or taper corticosteroids without a relapse. Safety was assessed by the occurrence of adverse events. Results 7 IRP patients (4 male, median age 41) with a median disease duration of 4 years (range: 1.25–9 years) were treated with Anakinra (median treatment duration: 20 months). All patients were resistant or intolerant to NSAIDs, Prednisone, Colchicine and at least one immunosuppressive or immunomodulatory drug such as AZA, Methotrexate, Plaquenil, or IVIG. The median number of recurrences before Anakinra was 6 (range: 4–7) and all patients were corticosteroid-dependent and had steroid-related side effects. After initiation of Anakinra, none of the patients had IRP relapse. Prednisone was tapered down to 5 mg/day or less in all patients. Four patients discontinued prednisone altogether. No significant adverse effects have occurred as a result of Anakinra treatment and all patients continued treatment after the study period. Conclusion Long-term Anakinra is a rapid-acting, efficient and safe steroid sparing agent even for patients with IRP refractory to previous immunosuppressive and/or immunomodulatory agents.

14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p 0.01), DAS4CRP (r = 0.46, p 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.

Background 14–3–3η is a protein that is overexpressed in serum and joint fluid of patients with rheumatoid arthritis (RA) and may represent a diagnostic biomarker for RA. Objectives We assessed the prevalence and serum levels of 14–3–3η in patients with RA and with other rheumatic diseases. Methods Serum levels of 14–3–3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases and in 66 healthy subjects. The RA group consisted of 51 patients with well-established RA who were treated with different DMARDs, and 45 patients with early untreated disease (onset of less than 1 year). The disease control group included 33 patients with systemic lupus erythematosus (SLE), 44 patients with ankylosing spondylitis (AS) and 24 psoriatic arthritis (PsA) patients. All of the sera samples were evaluated by JOINT stat 14–3–3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. Results Median (IQR) 14–3–3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075–3.11)] and in established RA patients [0.15 ng/ml (0.08–1.26)] in comparison with healthy subjects [0 ng/ml (0–0)] and disease controls: SLE [0.01 ng/ml (0–0.055)], AS [0.05 ng/ml (0–0.255)] and PsA [0.01 ng/ml (0–0.065)]. The prevalence of 14–3–3η positivity in early RA patients was 58%, significantly higher than in the disease control group (SLE: 9%, p Conclusions The concentration of 14–3–3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases and serve as an additional biomarker in the diagnosis of RA. Disclosure of Interest O. Shovman: None declared, B. Gilburd: None declared, A. Watad: None declared, H. Amital: None declared, P. Langevitz: None declared, N. L. Bragazzi: None declared, M. Adawi: None declared, D. Perez: None declared, G. Bornstein : None declared, M. Lidar : None declared, M. Blank: None declared, Y. Azuri: None declared, N. K. Biln Employee of: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp, Y. Shoenfeld: None declared

Background 14–3–3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). Objectives To assess the disease activity parameters and 14–3–3η protein concentrations in serum of early RA patients treated with Tofacitinib. Methods Paired serum samples from 35 previously non-treated early RA patients (disease onset less than 1 year) receiving Tofacitinib were obtained at baseline and 5 months after the initiation of treatment. Levels of 14–3–3η were measured by JOINT stat 14–3–3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. We investigated the correlation between changes in serum 14–3–3η concentrations and changes in clinical disease activity index (CDAI), simplified disease activity index (SDAI), Disease Activity Score (DAS) 4CRP and DAS4ESR. Results Increased concentrations of 14–3–3η were found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ±SD baseline 14–3–3η concentrations [4.92±8.86 ng/ml] were significantly higher (p=0.005) than those found following treatment [1.97±4.59 ng/ml]. Statistically significant improvement (p Conclusions The study demonstrates that decrease in 14–3–3η protein concentrations in RA patients treated with Tofacitinib is correlated with improvement of clinical disease activity parameters. 14–3–3η protein is a useful biomarker for monitoring Tofacitinib therapy. Disclosure of Interest O. Shovman: None declared, B. Gilburd: None declared, A. Watad: None declared, H. Amital: None declared, P. Langevitz: None declared, N. L. Bragazzi: None declared, M. Adawi: None declared, D. Perez: None declared, M. Blank: None declared, N. K. Biln Employee of: Augurex Life Sciences Corp, A. Marotta Employee of: Augurex Life Sciences Corp, Y. Shoenfeld: None declared

Specific inflammatory pathways and specifically Tumor Necrosis Factor alpha (TNF-α) have been associated with the neurodegeneration in Parkinson's disease (PD). TNFα is also known to play an important role in the pathogenesis of sarcoidosis and TNF blockers can ameliorate the disease. In contrast, multiple sclerosis (MS) is clearly exacerbated by anti- TNF-α medications. We have therefore hypothesized that Parkinson-like disease would be more common in neurosarcoidosis (NS) compared to MS. The aim of this case-control study was therefore to assess the frequency of extrapyramidal signs in patients with NS compared to MS patients. In order to do so the medical records of NS patients and of age and gender matched MS patients were reviewed and data regarding the clinical features, ancillary tests performed, treatment, and outcome were documented. Patients were then examined in a uniform manner for the presence of extrapyramidal signs. We found that in the NS group 8 patients had minor signs, one had mild functional disability and 3 subjects had significant extrapyramidal signs compatible with the diagnosis of Parkinson's disease. All extrapyramidal signs found in 5 of the MS group were minor. The proportional severity of extrapyramidal signs was significantly higher (p=0.045, chi square test) in the NS group compared to the MS group. We conclude that the specificity of extrapyramidal to NS raises the intriguing question of whether specific inflammatory pathways involving TNF-α play a role in the pathogenesis of PD and therefore may be a therapeutic target.

Objective Exertional leg pain is a characteristic musculoskeletal manifestation of familial Mediterranean fever (FMF). We aimed to define the frequency and characteristics of exertional leg pain in a large cohort of FMF patients and to evaluate for additional signs and symptoms of spondyloarthritis (SpA) in this patient population. Methods FMF patients were allocated into study or control groups based on the presence or absence of exertional leg pain. Randomly selected patients underwent magnetic resonance imaging (MRI) of the ankle as well as plain radiography of the sacroiliac joints. Results The prevalence of exertional leg pain among the 170 FMF patients included in the study was 58.2%. Patients with exertional leg pain had significantly more joint attacks (74.7% versus 40.8%; P < 0.0001), fever attacks (35.4% versus 15.5%; P = 0.004), and pleuritis attacks (48.5% versus 29.6%; P = 0.013) as well as more attacks per year. Elevations of inflammation markers were significantly more frequent among the study group (for the erythrocyte sedimentation rate, 44.4% of patients versus 21.1% of patients; P = 0.016) (for the C-reactive protein level, 48.4% of patients versus 31.8% of patients; P = 0.013), and M694V homozygosity was more prevalent among the study group (45.5% versus 21.1%; P = 0.001). Signs compatible with enthesopathy on MRI were observed in 73.5% of patients in the study group and in 33.3% of patients in the control group (P = 0.046). Definite SpA was diagnosed in 41.2% of the patients in the study group compared to none of the controls (P = 0.07) (odds ratio 1.7 [95% confidence interval 1.2–2.3]). Conclusion Exertional leg pain is a common manifestation of FMF and is a marker of a more severe disease phenotype. Additionally, exertional leg pain is frequently associated with sacroiliitis and an underlying ankle enthesopathy and should therefore be considered a new feature of SpA.

Localized scleroderma is traditionally considered to be limited to the skin, subcutaneous tissue, underlying bone, and in the craniofacial subtype, also nervous system involvement. However, recent studies have also described other systemic manifestations in these patients. Despite many reports of neurological involvement in patients with the craniofacial linear localized scleroderma, it is extremely rare in patients with the other subtypes of localized scleroderma. Here, we report an extraordinary case of localized scleroderma en plaque (classic morphea), located to the upper trunk and neck, associated with neurological manifestations presented as seizures. Magnetic resonance imaging of the brain showed focal lesions on the contralateral side to the skin involvement. This case is extremely relevant not only due to its rarity, but also because it supports the idea that the pathogenesis of the localized scleroderma is related to a systemic autoimmune process. • Localized scleroderma is known to be related with systemic symptoms. • To the best of our knowledge, this is the first case report of an exclusive plaque morphea with neurological involvement. • This case provides support to the concept that the pathogenesis of the disease is a systemic autoimmune process.

Aim To evaluate the effect of physical activity on the structural, morphological, and metabolic characteristics of the gastrocnemius muscle in familial Mediterranean fever (FMF) patients, utilizing quantitative 31 P magnetic resonance spectroscopy (MRS), in order to elucidate the mechanism of their exertional leg pain. Materials and methods Eleven FMF patients suffering from exertional leg pain (eight male, three female; mean age 33 years) and six healthy individuals (three male, three female; mean age 39 years) constituted the control group. All of the participants underwent magnetic resonance imaging (MRI) and non-selective 31 P MRS (3 T) of the leg muscles before and after graded exercise on a treadmill. Phosphocreatine (PCr):inorganic phosphate (Pi), PCr:adenosine triphosphate (ATP) ratios and the intracellular pH of the leg muscles were measured using 31 P MRS. Results For both groups, normal muscle mass with no signal alterations was observed on the MRI images after exercise. The normal range of pre- and post- exercise MRS muscle parameters was observed in both groups. However, the intracellular pH post-exercise, was significantly higher (less acidic) in the FMF group compared to the control group [pH (FMF) = 7.03 ± 0.02; pH (control) 7.00 ± 0.02; p Conclusions The finding of a less prominent, post-exercise acidification of the gastrocnemius muscle in this FMF patient group suggests a forme fruste of glycogenosis. This preliminary observation should be further investigated in a future, larger-scale study.

Granulomatosis and angiitis (GPA) is a multisystemic disease characterized by a granulomatous inflammation, tissue necrosis, and vasculitis of small and medium-sized blood vessels. Although the disease has a predilection for the upper respiratory tract, lungs, and kidneys, any organ system may be affected. Here, we present a case of generalized GPA manifested initially by necrotizing isolated parotitis and later by pulmonary–renal syndrome. Simultaneously with pulmonary hemorrhage, our patient developed an antiphospholipid syndrome (APS) presenting with deep vein thrombosis and strongly positive lupus anticoagulant. To the best of our knowledge the coincidence of parotitis and pulmonary–renal syndrome due to GPA and APS has never been reported previously. Concomitant venous thromboembolism may be life-threatening in a patient with GPA. Early diagnosis and institution of the proper therapy are critical in order to prevent organ damage.

Systemic sclerosis is a systemic, inflammatory, autoimmune disease affecting the skin and viscera, manifesting pathologically with microvascular lesions, perivascular infiltration by mononuclear cells and increased deposition of extracellular collagen. The rarity of the disease as well as its propensity to appear in the early 1940s, explain the low frequency of concurrent scleroderma and pregnancy. However, the marked female excess, as well as the trend for increasing maternal age due to social change and assisted reproductive technologies, renders heightened significance to issues of fertility, pregnancy course and pregnancy outcomes. In the past, scleroderma patients were thought to be at high risk for poor fetal and maternal outcome, but more current retrospective studies show that despite an increased frequency of prematurity and small for gestational age infants, overall maternal and neonatal survival is good. Hence, at present, with close monitoring and appropriate therapy most scleroderma patients can sustain a successful pregnancy. Therapy with hydroxychloroquine and low dose steroids as well as judicious use of intravenous immunoglobulins is permitted. Renal crisis remains the most dreaded complication of a scleroderma pregnancy and necessitates prompt institution of ACE inhibitor therapy despite its potential teratogenicity. In order minimize the risk for renal crisis, pregnancies should be avoided in rapidly progressive diffuse disease as such patients are at a greater risk for developing serious cardiopulmonary and renal problems early in the disease. This review shall focus on the bi-directional effects of scleroderma on fertility and pregnancy as well as on the management of pregnancy and delivery in the scleroderma patient.

Background ‘Erysipelas-like’ erythema (ELE) is a well recognized, although uncommon, manifestation of familial Mediterranean fever (FMF), which is frequently mistaken for infectious erysipelas, especially when forming the initial disease presentation. Aim To clinically and genetically characterize ELE as the first manifestation of FMF. Methods FMF patients with ELE as the first disease presentation (study group), were compared with FMF patients with ELE, appearing during the disease course (control group I), and to those FMF patients who never had ELE (control group II). Results Patients of the study group were comparable to patients without ELE with respect to all demographic, clinical and genetic features studied, and yet differed from patients with ELE appearing later in the disease course in disease severity score (1.7 ± 0.4 vs. 2.4 ± 0.6, P = 0.01), length of diagnosis delay (7.2 ± 6.4 vs. 2.3 ± 3.3 years, P=0.037), age of FMF onset (24.8 ± 19.9 vs. 5.6 ± 5.7 years of age, P=0.014) and rate of homozygosity to the M694V mutation (14.3% vs. 68.7% respectively). ELE traits in the study and control groups were alike. Conclusions FMF with ELE as the first disease manifestation form an uncommon subgroup, clinically and genetically diverging from the rest of the FMF-ELE patients.

Morphea and other scleroderma-like skin conditions are occasionally linked with exposure to chemical compounds such as silicone. We treated a 56-year-old woman with generalized severe skin induration accompanied with systemic symptoms and peripheral eosinophilia, which appeared 2.5 years after breast silicone implantation and abdominal liposuction. Blood test results and histopathological examination of her skin suggested the diagnosis of morphea overlapping with eosinophilic fasciitis. Her skin disease was presumed to be an autoimmune reaction to silicone implantation. While the removal of the implants did not improve her illness, treatment with 1 mg/kg prednisone and PUVA bath was initiated, with some improvement. This patient illustrates an example of ASIA (Autoimmune Syndrome Induced by Adjuvants), as her disease appeared following exposure to an adjuvant stimulus, with ‘typical’, although not well-defined, autoimmune manifestations.

Introduction MRI and MRA are used for diagnosis and activity determination of patients with Takayasu's arteritis (TA). However, there is a limited experience regarding the role of MRI in long-term follow-up of those patients. The aim of the present study was to evaluate the clinical usefulness of MRI in the long-term follow-up of patients with Takayasu's disease. Materials and methods The clinical data of 11 TA patients, who obtained two or more follow-up MRI scans, was matched with the imaging results. MRI examinations were considered positive for disease activity when one of the following findings was noted: new arterial wall enhancement or interval appearance of anatomical changes (interval dilatation, stenosis or occlusion or new arterial wall irregularity). Conversely, MRI examinations were considered to show signs of improvement when local enhancement disappeared, or when a stenosis was relieved. Disease activity was determined by the combination of worsening localizing ischemic signs and symptoms, systemic signs and symptoms (malaise, fever, etc.), and elevated blood markers (CRP and ESR). Results A total of 47 MRI examinations were performed in 11 patients (1 male, mean age 28, range 14–53 years) with a total follow-up time ranging between 12 and 56 months (average 36 months). MRI was positive for active disease at least once in nine out of the 11 patients (82%). The most commonly affected arteries were the aortic arch, the left subclavian artery and the left common carotid artery. No statistically significant correlation was found between clinical activity and MRI signs of activity. Conclusion Although MRI is a well established modality for primary diagnosis of TA, the present study suggests that it has a limited clinical role in the long-term follow-up of those patients when reactivation of disease is suspected.

Objective. To investigate whether in patients with antiphospholipid syndrome (APS), high positive antibody titers are associated with adverse pregnancy outcome. Design. A retrospective cohort study of prospectively collected data. Setting. Sheba Medical Center, Israel, a tertiary referral center. Population sample. Pregnant women with APS. Methods. Anticardiolipin, a-β2-glycoprotein I antibodies, and lupus anticoagulant were measured before pregnancy. Women were divided into those with antibody titers >four times the upper limit of normal (high positive titer, HPT group), and the rest, into the positive titer (PT) group. All women were treated with daily enoxaparin and aspirin. Main outcome measures. Composite adverse fetal/neonatal outcome, defined as one or more of the following: fetal/neonatal loss, preterm birth ≤32 weeks, and birthweight below than 10th percentile. Composite adverse fetal/neonatal outcome was compared between the HPT and PT groups. Maternal adverse outcomes were also compared. Results. 51 women with APS were followed during 55 pregnancies, 20 in the HPT and 35 in the PT groups. The two groups were similar with regard to previous obstetric and clinical characteristics. Among HPT women, only 7/20 (35%) pregnancies culminated in appropriately grown, live-born infants >32 weeks’ gestation, compared with 27/35 (77%) PT pregnancies. The risk of adverse fetal/neonatal outcome was 5.7 times higher (95%CI 1.9–17.7) for HPT than for PT women. Conclusions. Pregnant women with APS and high positive antiphospholipid antibody titers are a unique and extremely high risk group for adverse fetal/neonatal outcome. Stricter surveillance and possibly additional therapy options should be explored for this patient population.

The immune balance in patients with rheumatoid arthritis (RA), a disease characterized by TH1 dominance, treated by the preferred combined anti-tumor necrosis factor (anti-TNF) and methotrexate (MTX) therapy was evaluated by assessing the chemokine and cytokine receptors as well as apoptosis induction. A meta-analysis of combined therapy by TNF blockers and MTX in 15 RA patients, MTX monotherapy in 20 RA patients, and 11 diagnosed but untreated RA patients was performed by assessing several immune markers in the whole lymphocyte population, as well as in specific CD4 cells, by both flow cytometry and image analysis. A significant downregulation of CXCR3 and IL-12 receptors (both TH1 markers) and a significant increase in the chemokine receptor CCR4 and, to a lesser extent, IL-4R (both TH2 markers) were found; a particularly marked increase was found in patients treated by combined therapy. This phenomenon was pronounced in CD4 cells and was accompanied by a high proportion of apoptotic cells. The therapeutic effect of MTX and TNF blockers may be due to apoptosis induction in lymphocytes infiltrating from the inflammation site and restoring the TH1/TH2 balance.

There is a paucity of knowledge regarding the autonomic nervous system function in patients with familial Mediterranean fever (FMF). Therefore, our aim was to evaluate autonomic responses in patients with FMF using complementary tests. The study groups included 33 patients with uncomplicated FMF and 39 control subjects. Autonomic function was evaluated by measuring responses to metronomic breathing, the Valsalva maneuver, and the Ewing maneuver. Autonomic parameters were computed from electrocardiograms with designated computer software. There were no statistically significant differences in any of the measured parameters of autonomic function between the patient and control group. The measured autonomic parameters of both groups were similar to those previously reported in healthy individuals. In conclusion, patients with FMF who did not develop amyloidosis due to continuous colchicine treatment appeared to have normal autonomic function, as reflected by the normal response to physiological autonomic stimuli.

Quinine was first recognized as a potent antimalarial agent hundreds of years ago. Since then, the beneficial effects of quinine and its more advanced synthetic forms, chloroquine and hydroxychloroquine, have been increasingly recognized in a myriad of other diseases in addition to malaria. In recent years, antimalarials were shown to have various immunomodulatory effects, and currently have an established role in the management of rheumatic diseases, such as systemic lupus erythematosus and rheumatoid arthritis, skin diseases, and in the treatment of chronic Q fever. Lately, additional metabolic, cardiovascular, antithrombotic, and antineoplastic effects of antimalarials were shown. In this review, we discuss the known various immunomodulatory mechanisms of antimalarials and the current evidence for their beneficial effects in various diseases and in potential novel applications.

The aim of the study was to further evaluate repolarization dispersion in familial Mediterranean fever (FMF). Findings on 12-lead electrocardiography were compared with 32 patients with uncomplicated FMF and age- and sex-matched control subjects. All procedures followed stringent standards. Repolarization and dispersion parameters were computed with designated computer software, and results of the five beats were subsequently averaged. There were no statistically significant differences between the groups in average QT and average corrected QT interval length, average QT interval dispersion, average QT corrected dispersion, or QT dispersion ratio. During 6 months of follow-up, no cases of sudden death or arrhythmia were documented in either group. Patients with FMF who are continuously treated with low-dose colchicine and have not developed amyloidosis seem to have QT dispersion parameters similar to those of healthy subjects and therefore apparently have no increased risk of adverse cardiac events associated with abnormal repolarization.

Patients with systemic lupus erythematosus (SLE) produce antibodies to many different self-antigens. Here, we investigated antibodies in SLE sera using an antigen microarray containing many hundreds of antigens, mostly self-antigens. The aim was to detect sets of antibody reactivities characteristic of SLE patients in each of various clinical states – SLE patients with acute lupus nephritis, SLE patients in renal remission, and SLE patients who had never had renal involvement. The analysis produced two novel findings: (i) an SLE antibody profile persists independently of disease activity and despite long-term clinical remission, and (ii) this SLE antibody profile includes increases in four specific immunoglobulin G (IgG) reactivities to double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), Epstein–Barr virus (EBV) and hyaluronic acid; the profile also includes decreases in specific IgM reactivities to myeloperoxidase (MPO), CD99, collagen III, insulin-like growth factor binding protein 1 (IGFBP1) and cardiolipin. The reactivities together showed high sensitivity (> 93%) and high specificity for SLE (> 88%). A healthy control subject who had the SLE antibody profile was later found to develop clinical SLE. The present study did not detect antibody reactivities that differentiated among the various subgroups of SLE subjects with statistical significance. Thus, SLE is characterized by an enduring antibody profile irrespective of clinical state. The association of SLE with decreased IgM natural autoantibodies suggests that these autoantibodies might enhance resistance to SLE.

Objective. To characterize familial Mediterranean fever (FMF) in Ashkenazi patients, a Jewish subgroup in which FMF has rarely been described before.Methods. A retrospective analysis, comparing demographic, clinical, and genetic measures of the cohort of Ashkenazi Jewish patients with FMF (n = 57), followed at the National Center for FMF in Israel, to age and sex matched patients of Iraqi Jewish (n = 62) and North African Jewish (NAJ; n = 61) origin.Results. Age at disease onset and diagnosis was earlier in NAJ than among Ashkenazi and Iraqi patients. Family history of FMF was described by only 30% of Ashkenazi patients as opposed to the majority of Iraqi and NAJ patients (p = 0.001). The frequency of abdominal and febrile attacks was similar among the 3 groups, while chest and joint attacks were far less common in Ashkenazi and Iraqi compared to NAJ patients. A good response to colchicine was noted in a similar proportion of Ashkenazi and Iraqi patients (82–84%) as opposed to only 56% of NAJ patients (p = 0.0001). Proteinuria, renal failure, and amyloidosis were most frequent among the NAJ patients (18, 6.6, and 9.8% compared to 5.3, 0, and 3.5% and 1.6, 0, and 0% in Ashkenazi and Iraqi patients, respectively).Conclusion. Ashkenazi patients with FMF stand at the mildest end of the clinical spectrum of FMF. This is notwithstanding the tendency for amyloidosis, the frequency of which is not trivial and which deserves particular awareness.

The aim of this study was to reevaluate the role of infection in inflammatory bowel disease (IBD). Sera from 119 patients with IBD [80 with Crohn's disease (CD); 39 with ulcerative colitis] and 98 healthy controls were assessed using the Bio-Rad BioPlex 2200 for the presence of Toxoplasma gondii, cytomegalovirus, Epstein-Barr virus, Treponema pallidum, and Saccharomyces cerevisiae. Hepatitis B virus, hepatitis C virus (HCV), and anti-Helicobacter pylori antibodies were assessed by ELISA. In addition, sera were tested for a panel of antibodies associated with thrombophilia as well as various autoantibodies. Titers of antibodies toward HCV and T. gondii, and S. cerevisiae were higher in IBD patients than in controls, while the H. pylori autoantibodies were less prevalent among the patient population. Several thrombophilia-associated antibodies were more common in CD patients, and a single patient had a thromboembolic event. Our results show an excess of anti-HCV and anti-T. gondii antibodies among patients with IBD compared to healthy controls. Whereas the former may be the result of immunosuppression from the inflammatory disease itself or from the medications used to treat it, the latter association suggests that T. gondii is involved in the etiopathogenesis of IBD, and especially CD, in humans, as has been shown in the murine model. However, our findings also reiterate the positive association between CD and anti-S. cerevisiae antibodies as well as the negative association with H. pylori infections. These, in turn, lend indirect support to the "hygiene hypothesis" in IBD as well as the newly proposed role of commensal bacteria in the initiation of the disease process.

Sarcoidosis of the spinal cord is rare, even more so as the initial presentation of the disease. We describe six cases of spinal cord sarcoidosis and delineate a distinguishing feature which may allow for a timely diagnosis. All patients were admitted with complaints of a "corset-like" pressure in the lower chest and later developed cranial nerve palsies (two patients), parasthesias/paraparesis (two patients), fever of unknown origin (one patient), and bilateral proptosis (one patient). Serological tests, immunological screening, cerebrospinal fluid (CSF) analysis, bacteriological and viral testing were performed in all patients. Spinal and cerebral MRI, high-resolution computed tomography (HRCT) of the chest and gallium scan suggested the diagnosis of neurosarcoidosis of the spine while a biopsy of mediastinal lymph nodes, extra-ocular muscles, or spinal cord confirmed it. CSF showed inflammatory signs in 66% of patients and serum ACE levels were increased in a similar fraction. MRI revealed a gadolinium-enhanced thickening of the cord at the thoracic level in three patients whereas three other patients had normal spinal MRI despite similar symptoms. The presence of mediastinal lymphadenopathy on HRCT of the chest suggested the diagnosis in a third of patients. Patients were treated with steroid, immunosuppressive therapy and/or biologic therapies, with complete resolution in one case, improvement in four, and a somewhat deteriorating course, with development of spinal cord atrophy in the final case. As spinal cord involvement of sarcoidosis is extremely rare, making the diagnosis in the absence of systemic disease is challenging. The cases herein described suggest that sensory disturbance in a "corset-like" distribution may be indicative of neurosarcoidosis, especially when accompanied by extra-axial involvement such as cranial nerve palsies. This should prompt an evaluation for systemic involvement, keeping in mind that serum ACE and chest radiographs may be normal in the presence of primarily CNS-limited disease.

Serositis is a common clinical manifestation of systemic lupus erythematosus (SLE), as well as being the hallmark of familial Mediterranean fever (FMF), the most prevalent monogenic disease in the Jewish population. We have treated four patients who suffered from both SLE and FMF since 2001 in our clinic, which also serves as the national center for FMF. Our cases illustrate both similarities and dissimilarities between the clinical manifestations of these two diseases, an aspect which should be borne in mind, especially in the young female patients. In general, it seems that co-occurrence of FMF moderates the presentation of lupus.

Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.

Objectives. To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations.Methods. FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations.Results. Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site.Conclusions. Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.

The alpha1beta1 integrin, very late antigen (VLA)-1, characterizes collagen adherent interferon (IFN) gamma producing memory T cells in inflamed synovium. We now report that the mean percentage of VLA-1+ T cells is significantly lower among peripheral blood mononuclear cells of rheumatoid patients responsive to antitumor necrosis factor (TNF) alpha therapy than of those with active disease not receiving therapy. Neutralization of TNFalpha during in vitro polyclonal activation of VLA-1- T cells reduced differentiation to expression of VLA-1 and inhibited secretion of IFNgamma, but did not affect integrin expression on in vivo differentiated VLA-1+ T cells. Moreover, synovial fluids of patients relapsing during and after therapy were enriched in VLA-1+ T cells and lines derived from VLA-1+ T cells in peripheral blood of treated patients retained collagen binding and secreted IFN gamma. Thus, whereas therapy decreases VLA-1+ T cells in rheumatoid arthritis patients, a subset is resistant and contributes to residual and recurring inflammation.

Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with the persistence of lupus anticoagulant or anticardiolipin (aCL) antibodies. Accumulating evidence indicates that phospholipid binding protein, beta2-glycoprotein I (beta2GPI) represents the major target antigen for antiphospholipid (aPL) antibodies and plays a role in the pathogenesis of APS. It is widely accepted that aPL antibodies detected by conventional solid phase assays in patients with APS are mainly directed against a complex of aCL and anti-beta2GPI, although antibodies against beta2GPI protein can now also be detected by specific ELISA using purified proteins in solid phase. Despite the fact that these antibodies are not listed in the new diagnostic criteria, a high specificity of anti-beta2GPI assay for the clinical features of APS was established. During the last decade, numerous studies have investigated the clinical link between aCL and/or anti-beta2GPI antibodies and diverse features of APS. This manuscript reviews the current studies published recently in this field and discusses the relationship between the existence of aCL and anti-beta2GPI antibodies and the main and unusual manifestations of APS.

Hearing loss, both sensorineural and conductive, is a well-recognized manifestation of systemic vasculitis, yet has only infrequently been described as its initial presentation. We describe three cases in which hearing loss preceded the diagnosis of systemic vasculitis by a period of a few weeks to more than 6 months. While steroid therapy was initiated immediately in one of the cases, comprehensive immunosuppressive therapy was given only after additional manifestations compatible with vasculitis appeared, allowing for a diagnosis of Wegener's granulomatosis in two of the cases and undifferentiated vasculitis, in the third. Hearing improved in all patients, albeit, residual dysfunction remained. Prompt referral for a complete rheumatologic workup in cases of unexplained hearing loss would allow for a timely diagnosis of a collagen vascular disease and facilitate early initiation of systemic therapy, possibly yielding better audiological results.

We describe four women with idiopathic granulomatous mastitis, a rare benign disease. Age range was 32-40 years. Disease duration was less than 1 year in three patients and long term in the fourth. The diagnosis was based on histological findings, after extensive workup ruled out malignancy and known causes of granulomatous mastitis. Treatment with prednisone with gradual tapering yielded a good response. Clinicians should consider the possibility of idiopathic granulomatous mastitis in young women with inflammatory breast processes and negative findings on relevant biopsy, laboratory, and imaging studies. Glucocorticoids are the treatment of choice; surgery is not recommended. Some patients require a glucocorticoid-sparing drug.

Patients having systemic rheumatic diseases constitute a small percentage of admissions to the medical intensive care units (ICUs). Dermatomyositis (DM) is one of the rheumatic diseases that have secondary complications that may lead to a critical illness requiring hospitalization in the ICU. Herein, we present the features, clinical course, and outcome of critically ill patients having DM who were admitted to the ICU. The medical records of six DM patients admitted to the ICU in a large tertiary hospital in a 12-year period were reviewed. The mean age of patients at time of admission to the ICU was 38 (range 16-37). Mean disease duration from diagnosis to admission to the ICU was 1.6 years (range 1 month-8 years), while the main reason for admission to the ICU was acute respiratory failure. Two of six patients died during the hospitalization. The main causes of death were respiratory complications and sepsis. The outcome of DM patients admitted to the ICU was generally not different from the outcome of other patients hospitalized in the ICU. The main reason for hospitalization was acute respiratory failure. As there are many reasons for respiratory failure in DM, an early diagnosis and aggressive appropriate treatment may help to further reduce the mortality in these patients.

Behcet's disease (BD) is an inflammatory disorder of unknown cause, associated with vasculitis. Arterial or venous thrombosis occurs in about 25% of BD patients. Familial Mediterranean fever (FMF) is another inflammatory disorder, which stems from mutations in the FMF gene (MEFV) and shares a number of features with BD.MEFV analysis in patients with BD suggests that mutated MEFV may act as a susceptibility gene in BD. We studied the rate and the clinical correlates of MEFV mutations in Israeli BD patients.Included were 54 BD patients who satisfied the International Study Group criteria for BD. All BD patients were genotyped using polymerase chain reaction (PCR) and restriction enzyme analysis for the three most common MEFV mutations (M694V, V726A, and E148Q). The association between BD manifestations and MEFV alleles was analysed.Twenty-one BD patients were found to carry a single MEFV mutation and three additional patients were compound heterozygotes, a frequency significantly higher than that expected for ethnically matched healthy individuals. There were no statistically significant differences between carriers and non-carriers with respect to gender, frequency of HLA B5 antigen, cutaneous lesions, joint disease, and severity score. However, carriers did experience thrombosis more often [54% vs. 17%, p0.005, odds ratio (OR) = 6.9, 95% confidence interval (CI) 1.75-26.9] and uveitis less often (20% vs. 40%, p0.05, OR = 0.2, 95% CI 0.04-0.92).MEFV appears to be a susceptibility and modifier gene in BD.

The coexistence of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) named Rhupus is an unusual clinical condition. Previous reports mentioned that Rhupus patients have prominent RA-associated clinical manifestations and only mild organic damage related to SLE. Progressive or life-threatening manifestations are rare in Rhupus patients. Three patients with Rhupus are described in this article. Two of them presented antiphospholipid syndrome (APS) in addition to Rhupus. Also, we searched for similar cases in published literature. We present three patients with Rhupus syndrome. One of the patients has only Rhupus, the second patient has Rhupus and APS, and the third patient has Rhupus accompanied by severe Raynaud’s syndrome with digital ulcers, APS, pulmonary hypertension and two malignancies. Several studies have shown that Rhupus patients have an increased prevalence of positive antiphospholipid antibodies that resembles SLE. However, the presence of these antibodies is not associated with APS. There is only one case of Rhupus with secondary APS in which the patient presented headache and papilloedema due to cerebral venous thrombosis. Secondary Raynaud’s syndrome is rare in Rhupus patients, and to the best of our knowledge, only three cases of this are mentioned in literature. Secondary pulmonary hypertension and malignancies were never reported before in Rhupus patients. Rheumatologists should be aware of the possibility that Rhupus may be accompanied by progressive or life-threatening conditions such as APS, severe Raynaud’s syndrome with digital ulcers, pulmonary hypertension, or malignancies.

Inflammatory bowel disease, a collective term for ulcerative colitis and Crohn's disease, is a chronic, immune-mediated disease of the gastrointestinal tract that develops in genetically susceptible individuals. The role of infection in the development of inflammatory bowel disease is underscored by various clinical observations, such as the delayed age of onset, suggesting that childhood exposure to pathogens is essential, and the clinical improvement that follows decreasing bacterial intestinal load. Over the years, many a pathogen has been linked to the development and exacerbation of inflammatory bowel disease, notably; Mycobacterium paratuberculosis, Escherichia coli, Listeria monocytogenes and Chlamydia as well as viruses such as measles, mumps, rubella, Epstein-Barr virus and cytomegalovirus. Presently, leading theories of disease pathogenesis suggest loss of immune tolerance to normal commensal bacteria coupled with excessive exposure to bacterial antigenic products. This review describes the most commonly implicated pathogens in the causation of IBD and presents the evidence supporting their pathogenic role as well as data that offset their importance.

Patients with autoimmune diseases often present with olfactory impairment. The aim of the study was to assess the olfactory functions of female patients with fibromyalgia (FM) compared with patients with systemic sclerosis (SSc) and with healthy female controls. Olfactory functions were assessed in 24 patients with FM, 20 patients with SSc and 21 age-matched healthy controls. The sense of smell was evaluated using the Sniffin' Sticks test including the three stages of smell: threshold, discrimination, and identification (TDI) of the different odors. The severity of fibromyalgia was assessed using the fibromyalgia impact questionnaire (FIQ). The short form 36 (SF-36) questionnaire was also completed in order to seek a relationship between the patients perception of quality of life and the different aspects of the smell sense. Depression was evaluated in both FM and SSc patients utilizing the Beck depression inventory-II (BDI-II) questionnaire. Patients with FM had significantly lower TDI smell scores compared with both SSc patients and healthy controls (p < 0.005, One-Way ANOVA). Hyposmia (defined as TDI scores below 30) were observed in 14 of 24 (42 %) patients with FM compared to 3 of 20 (15 %) patients with SSc and 1 of the healthy controls (4.3 %) (p < 0.02). FM patients had significantly lower thresholds of smell compared to both healthy controls and patients with SSc (p < 0.001), whereas for patients with SSc only the ability to discriminate between odors was impaired (p < 0.006). We could not detect any statistical correlation between smell abilities and clinical manifestation of SSc or the FIQ and SF-36 scores among FM patients. However the correlation between depression, defined by the BDI-II score, and the sense of smell differed between patients with FM and patients with SSc. As only among SSc patients a lower sense of smell correlated with a higher BDI-II score (p = 0.02). Our findings suggest that there is a decrease in the sense of smell both in FM and SSc patients compared with healthy controls. However these impairments differ between patients group and might represent different mechanisms that affect the sense of smell.

One of the adverse events of tocilizumab (TCZ) is a transient, dose-dependent neutropenia. The recommendations of the Summary of Product Characteristics state that this neutropenia should be managed according to the absolute neutrophil count (ANC). However, the approach to a patient who had a history of neutropenia induced by previous DMARDs and developed TCZ-induced neutropenia remains unclear. We would like to report a series of four patients with rheumatoid arthritis who developed Grade 2 neutropenia (ANC 1-1.5 × 10(9)/L) following intravenous TCZ treatment at a dose of 8 mg/kg. All of them had a previous history of neutropenia (Grade 2 or Grade 3) due to Etanercept (three patients) and Sulfasalazine (one patient). Therefore, we decided to decrease the TCZ dosage by 10-20% approximately. Reducing of the dosage did not have any influence on the efficacy of TCZ, and all of our patients remained in clinical remission. The mechanisms underlying neutropenia induced by Tocilizumab, Etanercept and Sulfasalazine are also discussed in this article.

Background: Pyrin is a newly recognised intracellular regulator of inflammation, and mutations in MEFV, the gene encoding pyrin, are the cause of familial Mediterranean fever. Objective: To determine if known mutations of MEFV are associated with rheumatoid arthritis (RA) morbidity or can modify RA severity. Methods: The frequency of the three most common MEFV mutations: M694V, V726A, and E148Q, was determined in 98 Israeli patients with RA (74 women, 24 men) and compared with that in 100 healthy subjects matched for origin. RA severity was determined using a new clinical score of 126 grades. The median severity score of mutation carrier and non-carrier groups was compared after confounding measures were eliminated by logistic regression. Results: 17/98 (17%) patients with RA (all women) were heterozygous for common MEFV mutations, predominantly E148Q (12 patients), and one patient was homozygous for the V726A mutation. The overall mutation rate was comparable between patients with RA and healthy subjects. Patients carrying a mutation had a higher median severity score than the non-carrier group (42 v 29, p = 0.0005). The logistic regression model assigned a 15-fold odds ratio for severe RA in carriers, after adjusting for sex, presence of rheumatoid factor, age at onset, and disease duration (n = 97, p = 0.01, 95% CI 1.74 to 128). Conclusion: MEFV, and particularly the E148Q mutation, is an independent modifier of the clinical manifestations of RA. This is the second Th1-type autoimmune disease in which MEFV mutations have been shown to aggravate the clinical status.

Multiplexed assays using fluorescence microspheres is an exciting technology with multiple applications including the detection of antinuclear autoantibodies (ANA) and autoantibody profiles. It is a rapid, sensitive and automatic method for simultaneous quantitative detection of several autoantibodies. The aim of our study was to determinate ANA and other autoantibodies to the nine extractable nuclear antigens by the AtheNA Multi-Lyte ANA system and compare the results achieved by this method to the routinely used enzyme immunoassay.Four hundred eighteen serum samples were tested utililizing the multiplexed method: 96 healthy donors, 86 requested ANA specimens obtained from routine lab, and 236 samples from patients with known autoimmune diseases (43-scleroderma, 113-systemic lupus erythematosus, 38-Sjogren's syndrome, and 42 rheumatoid arthritis). The ANA and antibodies to nine different analytes (SS/A, SS/B, Sm, RNP, Jo-1, Scl-70, dsDNA, Centromere B and Histone) were tested.ANA screening by AtheNA system revealed high concordance of 99 and 97.7% with the enzyme immunoassay test in samples obtained from healthy donors and ANA requested samples, respectively. Evaluation of autoimmune disease-related samples for ANA by AtheNA technology also confirmed a high rate of concordance of 92-97.7% and correlated with the enzyme immunoassay. Positive discrepant results were found for Scl-70 specificity in 12.7% of SLE specimens by AtheNA technology, while all tested sera were negative for this antibody by enzyme immunoassay. Negative discrepant results were observed by the AtheNA system for anti-dsDNA. The sera (15 randomly obtained samples from SLE patients) were positive for anti-dsDNA in 50% of samples in Farr assay and 55% in enzyme immunoassay, respectively.We suggest that the AtheNA technology may be a useful diagnostic tool for ANA screening. Additional investigations are required to compare an analytic performance between AtheNA and routine methods in determination of the individual autoantibody profile.

Systemic lupus erythematosus (SLE) is a multi-systemic autoimmune disease leading to immunological aberrations and excessive multiple autoantibody production. The aim of this study was to investigate the prevalence of multiple autoantibodies in SLE patients utilizing the multiplex system method.We analyzed the presence of elevated titers of anti-Ro, anti-La, anti-RNP, anti-Sm, anti-Jo1, anti-centromere, anti-Scl-70, anti-histone, and anti-dsDNA antibodies in 199 serum samples (113 SLE patients, 86 healthy donors). We compared the type, level and number of autoantibodies and the correlation between the autoantibody profile and disease severity utilizing the SLEDAI score.Elevated titers of at least one autoantibody were detected in 48% of 42 SLE patients. Elevated titers of anti-Ro antibodies were most commonly detected. The distribution of specific autoantibodies was: anti-Ro- 23.8%, anti-dsDNA- 19%, anti-histone- 19%, anti-RNP- 14.2%, anti-La antibodies- 11.9%, anti-Sm- 7.1%, anti-Scl 70-4.7%, and anti-centromere- 2.4%. Utilizing ROC analysis, the sensitivity and specificity of anti-DNA antibodies at a cutoff value of 34 IU/ml were 87.1% and 79.4% respectively. Elevated titers of anti-Jo1 antibody were not detected. There was a correlation with the titer of anti-Ro antibodies and disease activity by the SLEDAI score. Seven patients harbored one autoantibody only, 15 patients harbored 2-3 autoantibodies, 3 patients harbored 4-5 autoantibodies, and one patient harbored 6 autoantibodies. A correlation between the number of autoantibodies per patient and disease severity was found. One patient with a multitude of autoantibodies had severe lupus and a myriad of clinical manifestations.In conclusion, the multiplex system is specific and sensitive, provides an autoantibody profile in a single test, and may be useful as a diagnostic test for SLE. Elevated anti-Ro antibodies are associated with severe disease. An autoantibody load may be indicative of more severe disease.

Anti-tumour necrosis fector [TNF] alpha treatment is known to carry the risk of promoting drug-induced lupus in patients with inflammatory bowel disease [IBD]. This manifests in most cases as asymptomatic elevation of anti-nuclear antibody titre, but can also rarely culminate in frank symptomatic lupus.1 However, whether this risk is a sine qua non for lupus being a contraindication for anti-TNF treatment in IBD, is not established.2 We report a patient with systemic lupus erythematousis [SLE] and with ulcerative colitis [UC], whose treatment with infliximab may provide preliminary insight on this clinical dilemma. The patient was a 35-year-old female with left-sided UC diagnosed 16 years before presentation. She had been treated …

The objectives of this study were to test the in vitro response of healthy non-activated, activated, and rheumatoid arthritis (RA) lymphocytes to methotrexate (MTX), and design an in vitro model for predicting the efficiency of MTX treatment for RA patients. Considering the RA profile of clonal-expanded CD4(+) T cells, phytohemagglutinin-activated mononuclear cells taken from healthy donors were incubated with different concentrations of MTX. The MTX-immunosuppressive effect was tested by fluorescence intensity measurements, including PI assay and annexin V assay. For simple detection, we used the Individual Cell Scanner (IC-S), which enables the measurement of early events in individual cells. Healthy mononuclear cells (MNC), and MNC derived from RA patients, were tested by the IC-S while utilizing fluorescence polarization (FP) measurements of fluorescein diacetate (FDA) as an established marker of activation or suppression. In healthy activated MNC, we found that MTX, through its early incubation period, interferes with the activation signal obtained by PHA and exerts an apoptotic signal, which is noted by increases in the FP. Comparing our model to six long-standing RA patients and five newly-diagnosed patients revealed significant differences in the FP measurements, including fluorescence depolarization as an early established measurement of lymphocyte activation, and hyperpolarization as a measurement of an early immunosuppressive effect. We conclude that MTX, an effective therapy for RA patients, could easily be tested by fluorescence polarization measurements of FDA before (or during) clinical use in order to predict its efficiency on a specific RA patient. Moreover, the FP measurements can be used for the diagnosis, and making timing and dosage decisions.

Crohn disease and familial Mediterranean fever (FMF) are inflammatory diseases characterized by abdominal pain and fever. The concurrence of the 2 diseases (FMF-CD) may pose a challenge to diagnosis and treatment. We undertook the present study to determine the prevalence of Crohn disease in FMF and to characterize FMF-CD patients clinically and genetically. Using a computerized search, the patients of our FMF clinic were screened for a concomitant diagnosis of Crohn disease. Patients and their medical records were thoroughly examined, and their DNA was genotyped for mutations in the MEFV gene. Control groups of ethnically and sex-matched patients suffering from each of the diseases alone, either Crohn disease or FMF, were used for comparison. We identified 7 patients with concomitant Crohn disease and FMF, which is more than the expected prevalence in the general population (p = 0.03). Crohn disease presented at a significantly later age in the FMF-CD group (40.6 +/- 10.0 yr versus 26.2 +/- 11.4 yr; p < 0.004). Disease severity and other characteristics of Crohn disease were comparable to the Crohn disease control group. Contrary to the FMF control group patients, FMF in FMF-CD patients was characterized by a higher attack frequency (p < 0.05) and increased prevalence of amyloidosis (p < 0.02). The overall severity score was similar in both groups. In conclusion, Crohn disease appears to be more prevalent in FMF and presents later than in patients without FMF. FMF in this group of patients shows a higher attack frequency and is more often complicated by amyloidosis.

Lung involvement in FMF is limited mainly to transient pleuritis during acute attacks. Amyloidosis of the lung is rare and is associated with symptomatic involvement of other organs while remaining subclinical in itself. Vasculitis of the lung in FMF is possible because of the strong association between FMF and a variety of vasculitides. With the exception of one case of isolated pulmonary vasculitis, vasculitis of the lung in FMF has not been described. The claim that FMF protects against asthma has not been established, but this inverse association, if present, may be traced to linkage disequilibrium in which MEFV modifies the effect of asthma and atopic-related genes, or to eosinophil function. Mesothelioma has been reported in at least four patients with FMF and is related to chronic or recurrent stimulation of the serous membrane. Three patients had peritoneal mesothelioma, while one developed mesothelioma of the lung. Finally, thromboembolism should be considered, particularly in patients with FMF amyloidosis who present with respiratory distress.

Objective.To evaluate the maternal and fetal outcome in a cohort of women undergoing a subsequent pregnancy after a previous cerebrovascular event in the presence of thrombophilia. Patients. Fifteen pregnancies were followed up in 12 women with past cerebrovascular events and thrombophilic disorders. The cerebrovascular events occurred during a previous pregnancy in five patients. Six patients had a bad obstetric history including intrauterine fetal death in four cases, early onset of severe preeclampsia in two cases and one infant that was small for gestational age. The thrombophilic disorders included: anti–phospholipid syndrome, protein C, S or antithrombin III deficiencies, mutations of the methyltetrahydrofolate reductase (MTHFR). All patients received prophylactic treatment with low molecular weight heparin and low dose aspirin. Results. Thromboembolic complications occurred in four pregnancies. Postpartum complications occurred in one patient; deep vein thrombosis and pulmonary emboli after stopping anticoagulation treatment. No patient had long-term neurologic damage. All pregnancies except one resulted in live births. (mean gestational age at delivery 36 ± 3. 7 weeks, mean birth weight 2656 ± 811 g). The one remaining pregnancy was electively terminated. There was one neonatal death due to the complications of severe prematurity in a woman with severe HELLP syndrome. Conclusion. This preliminary data suggests that women with a history of cerebrovascular events and thrombophilic disorders receiving prophylactic treatment, have a relatively favorable pregnancy outcome, however, they remain at significant risk during pregnancy further studies are necessary to determine the optimal prophylactic treatment.

Systemic lupus erythematosus (SLE) is an autoimmune disease that can attack many different body organs; the triggering event is unknown. SLE has been associated with more than 100 different autoantibody reactivities - anti-dsDNA is prominent. Nevertheless, autoantibodies to dsDNA occur in only two-thirds of SLE patients. We previously reported the use of an antigen microarray to characterize SLE serology. We now report the results of an expanded study of serology in SLE patients and scleroderma (SSc) patients compared with healthy controls. The analysis validated and extended previous findings: two-thirds of SLE patients reacted to a large spectrum of self-molecules that overlapped with their reactivity to dsDNA; moreover, some SLE patients manifested a deficiency of natural IgM autoantibodies. Most significant was the finding that many SLE patients who were negative for autoantibodies to dsDNA manifested abnormal antibody responses to Epstein-Barr virus (EBV): these subjects made IgG antibodies to EBV antigens to which healthy subjects did not respond or they failed to make antibodies to EBV antigens to which healthy subjects did respond. This observation suggests that SLE may be associated with a defective immune response to EBV. The SSc patients shared many of these serological abnormalities with SLE patients, but differed from them in increased IgG autoantibodies to topoisomerase and centromere B; 84% of SLE patients and 58% of SSc patients could be detected by their abnormal antibodies to EBV. Hence an aberrant immune response to a ubiquitous viral infection such as EBV might set the stage for an autoimmune disease.