The cellular immune response to influenza vaccination is preserved in rheumatoid arthritis patients treated with rituximab.

OBJECTIVES: Yearly vaccination against influenza is currently recommended to patients with rheumatoid Arthritis (RA). Antibody and cell-mediated responses are both involved in the defense against influenza. Humoral responses to influenza vaccine are impaired in RA patients treated with rituximab (RTX). The objectives of this study were to comparatively assess cell mediated and humoral responses to influenza vaccination in RA patients with or without RTX-induced CD20 B-cell depletion. METHODS: Trivalent influenza subunit vaccine was administered to 46 RA patients and to 16 healthy controls. The RA group included 29 patients treated by RTX and 17 on conventional disease-modifying anti-rheumatic drugs (DMARDs), mostly methotrexate. Peripheral blood mononuclear cells and sera were obtained immediately before and 4-6 weeks after vaccination. Cell-mediated response to influenza antigens was evaluated by flow cytometry for activated CD4 T-cells. Humoral response was evaluated by haemagglutination inhibition assay. RESULTS: Cellular response: Cell-mediated responses were comparable in RTX-treated vs. DMARDs-treated patients. The recall postvaccination CD4+ cellular response was similar in RA patients and healthy controls. A positive correlation was found between CD19+ cell count on the day of vaccination and cellular response in RTX-treated RA patients. Humoral response: The antibody response rate was significantly impaired in the RTX group: being 26.4%, 68.4% and 47.1% in RTX-treated, DMARDs-treated and controls, respectively. CONCLUSION: Cellular immunity to influenza vaccination in RTX-treated patients was similar to DMARDs-treated patients and healthy controls, while humoral immunity was severely impaired. The preservation of cellular immunity may explain the relatively low rate of infection among B-cell depleted patients.

Decreased levels of CCR3 in CD4+ lymphocytes of rheumatoid arthritis patients.

OBJECTIVES: To evaluate the expression of CCR3 receptors as well as CCR3 agonists, including eotaxin-2 and RANTES, among patients suffering from rheumatoid arthritis and healthy controls, as a possible pathogenetic mechanism in inflammatory joint disease. METHODS: Twenty-two patients and 13 healthy controls were recruited and clinically evaluated. CCR3 expression on CD4+ lymphocytes and mononuclear cells was evaluated by FACS analysis after staining with human CD4 APC (bioscience) and human CCR3 (CD193)PE. Levels of eotaxin-2 and RANTES were analysed by ELISA. RESULTS: A significant decrease was observed in the level of CD4+ cells expressing the CCR3 receptor in serum of RA patients (0.96+/-0.5) as compared with healthy controls (1.48+/-0.6) (p<0.05). A significant decrease in serum eotaxin-2 levels was evident among RA patients suffering from active disease, defined by a DAS-28 score above 5.5, compared with RA patients with lower activity scores (2.1+/-1.6 vs. 7.0+/-5.1; p=0.01). A significant decrease was evident in the number of CCR3 expressing Monocytes among RA patients treated with steroids and anti TNF-a medications as compared with RA patients not receiving such treatment. CONCLUSIONS: CCR3 is differentially expressed on inflammatory cells in RA, while eotaxin-2, a potent CCR3 agonist, is differentially expressed in active disease. Anti-inflammatory medications may down-regulate CCR3 expression in RA. The CCR3-CCR3 agonist pathway may thus have a pathogenic role in RA and may be a future target for novel treatment modalities.

Vaccination against influenza in patients with rheumatoid arthritis: the effect of rituximab on the humoral response.

OBJECTIVE: To assess the effect of rituximab on the efficacy and safety of influenza virus vaccine in patients with rheumatoid arthritis (RA). METHODS: The study group comprised patients with RA treated with conventional disease-modifying drugs with or without rituximab. Split-virion inactivated vaccine containing 15 microg haemagglutinin/dose of B/Shanghai/361/02 (SHAN), A/New Caledonian/20/99 (NC) (H1N1) and A/California/7/04 (CAL) (H3N2) was used. Disease activity was assessed by the number of tender and swollen joints, duration of morning stiffness and evaluation of pain on the day of vaccination and 4 weeks later. CD19-positive cell levels were assessed in rituximab-treated patients. Haemagglutination inhibition (HI) antibodies were tested and response was defined as a greater than fourfold rise 4 weeks after vaccination or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated in all subjects. RESULTS: The participants were divided into three groups: RA (n = 29, aged 64 (12) years), rituximab-treated RA (n = 14, aged 53 (15) years) and healthy controls (n = 21, aged 58 (15) years). All baseline protective levels of HI antibodies and GMT were similar. Four weeks after vaccination, there was a significant increase in GMT for NC and CAL antigens in all subjects, but not for the SHAN antigen in the rituximab group. In rituximab-treated patients, the percentage of responders was low for all three antigens tested, achieving statistical significance for the CAL antigen. Measures of disease activity remained unchanged. CONCLUSION: Influenza virus vaccine generated a humoral response in all study patients with RA and controls. Although the response was significantly lower among rituximab-treated patients, treatment with rituximab does not preclude administration of vaccination against influenza.

Vaccination against influenza in rheumatoid arthritis: the effect of disease modifying drugs, including TNF alpha blockers.

OBJECTIVE: To assess the efficacy and safety of vaccination against influenza virus in patients with rheumatoid arthritis, with special emphasis on the effect of disease modifying antirheumatic drugs (DMARDs), including tumour necrosis factor alpha (TNFalpha) blockers. METHODS: 82 rheumatoid patients and 30 healthy controls were vaccinated with a split-virion inactivated vaccine containing 15 mug haemagglutinin (HA) per dose of each of B/Hong Kong/330/2001 (HK), A/Panama/2007/99 (PAN), and A/New Caledonian/20/99 (NC). Disease activity was assessed by tender and swollen joint count, morning stiffness, evaluation of pain, Health Assessment Questionnaire, ESR, and C reactive protein on the day of vaccination and six weeks later. Haemagglutination inhibiting (HI) antibodies were tested by a standard WHO procedure. Response was defined as a fourfold or more rise in HI antibodies six weeks after vaccination, or seroconversion in patients with a non-protective baseline level of antibodies (<1/40). Geometric mean titres (GMT) were calculated to assess the immunity of the whole group. RESULTS: Six weeks after vaccination, a significant increase in GMT for each antigen was observed in both groups, this being higher in the healthy group for HK (p=0.004). The percentage of responders was lower in rheumatoid patients than healthy controls (significant for HK). The percentage of responders was not affected by prednisone or any DMARD, including methotrexate, infliximab, and etanercept. Indices of disease activity remained unchanged. CONCLUSIONS: Influenza virus vaccine generated a good humoral response in rheumatoid patients, although lower than in healthy controls. The response was not affected by the use of prednisone or DMARDs.

The effects of Zintona EC (a ginger extract) on symptomatic gonarthritis.

OBJECTIVE: Evaluation of the effect of a ginger extract (Zintona EC) on patients suffering from gonarthritis. MATERIAL AND METHODS: Twenty-nine patients (6 men and 23 women) with symptomatic gonarthritis (ACR criteria), in the age range 42-85 years, were included after randomization in a double blind, placebo controlled, crossover study of 6 months' duration. The treatment group was given a ginger extract (250 mg of Zingiberis Rhizoma per capsule, qid), while the placebo group received the same number of identical looking capsules per day. The crossover occurred after 3 months of therapy. Results were evaluated by a 100mm visual analog scale (VAS) of pain on movement and of handicap. RESULTS: Eight patients dropped out because of inefficacy, three from group 1 (ginger extract first) and five from group 2 (placebo first). One patient from group 1 and one from group 2 dropped out because of heartburn (while they were on ginger extract). Twenty patients completed the study period of 24 weeks and 19 that of 48 weeks follow-up. By the end of 24 weeks there was a highly statistically significant difference between the VAS of pain and handicap of the two groups (P<0.001). However, at crossover both groups showed a statistically significant decrease in VAS of pain on movement and of handicap, but the differences between the groups did not reach statistical significance. CONCLUSIONS: Zintona EC was as effective as placebo during the first 3 months of the study, but at the end of 6 months, 3 months after crossover, the ginger extract group showed a significant superiority over the placebo group.

Efficacy and safety of diacerein in osteoarthritis of the knee: a double-blind, placebo-controlled trial. The Diacerein Study Group.

OBJECTIVE: To evaluate the efficacy and safety of diacerein, a drug with interleukin-1beta--inhibitory activity in vitro, in patients with knee osteoarthritis (OA). METHODS: A total of 484 patients fulfilling the American College of Rheumatology criteria for knee OA were enrolled in this 16-week, randomized, double-blind, placebo-controlled, parallel study group with 3 diacerein dosages of 50 mg/day, 100 mg/day, and 150 mg/day (administered twice daily). RESULTS: In the intent-to-treat population, 100 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).

Insufficiency fractures in rheumatic patients: misdiagnosis and underlying characteristics.

OBJECTIVE: To report 9 patients with rheumatic diseases referred to our observation due to presumed exacerbation of their rheumatic disease, subsequently diagnosed as stress insufficiency fractures, and to characterize the clinical profile of patients prone to this complication. METHODS: The medical history of the patients was reviewed with special emphasis on their rheumatic disease, its course, duration and management, their menopausal state, location and characteristics of the fracture, its presentation and the initial presumed diagnosis, the delay in diagnosis, imaging diagnostic tests performed and outcome. Three representative case reports are presented. RESULTS: All 9 patients were women, 8 of them aged 50 years old or more, 8 with rheumatoid arthritis and 1 with polymyalgia rheumatica. They were all treated with corticosteroids and had reduction in their bone mass density when evaluated. Three of the patients presented with subcapital fracture of the femur, 4 had fractures of metatarsal bones and 2 had fractures of the distal tibia. In only one patient was a stress fracture initially suspected. Diagnosis was delayed by a mean of 31 days. CONCLUSION: The diagnosis of stress fractures in patients with rheumatic diseases may often be delayed or missed, and thus improperly treated. Increased awareness of this entity is of importance for prompt diagnosis and correct management.

Immediate and delayed effects of treatment at the Dead Sea in patients with psoriatic arthritis.

The purpose of this study was to evaluate the immediate and delayed effects of balneotherapy at the Dead Sea on patients with psoriatic arthritis (PsA). A total of 42 patients with PsA were treated at the Dead Sea for 4 weeks. Patients were randomly allocated into two groups: group 1 (23 patients) and group 2 (19 patients). Both groups received daily exposure to sun ultraviolet rays and regular bathing at the Dead Sea. Group 1 was also treated with mud packs and sulfur baths. Patients were assessed by a dermatologist and a rheumatologist 3 days before arrival, at the end of treatment, and at weeks 8, 16, and 28 from the start of treatment. The clinical indices assessed were morning stiffness, right and left hand grip, number of tender joints, number of swollen joints, Schober test, distance from finger to floor when bending forward, patient's self-assessment of disease severity, inflammatory neck and back pain and psoriasis area and severity index (PASI) score. Comparison between groups disclosed a similar statistically significant improvement for variables such as PASI, morning stiffness, patient self-assessment, right and left grip, Schober test and distance from finger to floor when bending forward. For variables such as tender and swollen joints, and inflammatory neck and back pain, improvement over time was statistically significant in group 1. Addition of mud packs and sulfur baths to sun ultraviolet exposure and Dead Sea baths seems to prolong beneficial effects and improves inflammatory back pain.

Validation study of a Hebrew version of WOMAC in patients with osteoarthritis of the knee.

The aim of the study was to validate a translated version of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) in Hebrew speaking populations. The WOMAC was translated into Hebrew from its English version and its reliability and validity were studied. Before its use in patients, the Hebrew version was translated back into English by an independent translator and minor amendments were made to satisfy the original English versions designed by Bellamy et al. The Hebrew version of the WOMAC questionnaire was administered to 114 patients with osteoarthritis of the knee. All the subjects were asked about the presence and severity of pain during movement and handicap, using a visual analogue scale (VAS) of pain and handicap. Test-retest reliability was assessed using Pearson's and intraclass correlation coefficients. Internal consistency was evaluated by Cronbach's alpha coefficient of reliability. Construct validity was tested by correlating the WOMAC items with VAS of pain and handicap. The test-retest reliability Pearson's correlation coefficients for the WOMAC items ranged from 0.55 to 0.78 (p<0.01), and the Cronbach's alpha was 0.97 at time 1 and 0.98 at time 2. Significant correlations (p<0.01) were obtained between the WOMAC items and VAS of pain and handicap. The Hebrew version of WOMAC is a reliable and valid instrument for evaluating the severity of osteoarthritis of the knee in Israeli patients.

Spa therapy for gonarthrosis: a prospective study.

The objective of this study was to evaluate the effect of spa therapy on clinical parameters of patients with gonarthrosis. Patients with gonarthrosis (n = 33) underwent a 2-week spa therapy using three treatment regimes and a 20-week follow-up as follows: group I (n = 11) had mineral water baths and hot native mineral mud packs, group II (n = 12) had mineral water baths and rinsed mineral-free mud packs and group III (n = 10) had tap water baths and mineral-free mud packs. The patients and the assessing rheumatologist were blinded to the difference in the treatment protocols. A significant improvement in the index of severity of the knee (ISK), as well as night pain scores, was achieved in group I. Improvement in physical findings and a reduction in pain ratings on a visual analogue scale (VAS) did not reach statistical significance. Analgesic consumption was significantly decreased in both groups I and III for up to 12 weeks. Global improvement assessed by patients and physician was observed in all three groups up to 16 weeks but persisted to the end of the follow-up period in group I only. Patients with gonarthrosis seemed to benefit from spa therapy under all three regimes. However, for two parameters (night pain and ISK) the combination of mineral water baths and mud packs (group I) appeared to be superior.

Ulnar translation of the scaphoid: an early X-ray sign of rheumatoid arthritis.

The distance between the os trapezium and radius (which we called scaphoid distance) became shorter during the course of rheumatoid arthritis (RA). Measurement of this distance was performed in 600 hands (300 patients), using standard position of patient's hand in supination with permanent angle (15-20%) between the axis of the radius and the axis of the third metacarpal bone (scaphoid distance). This provided a stable distance between the most distal point of the radial styloid process and most proximal point of the os trapezium. The patients were divided into two groups: a control group consisting of 100 patients with no inflammatory joint disease, and a group of 200 patients suffering from RA. Patients suffering from RA with bone erosions had smaller scaphoid distance than those suffering from RA without bone erosions. The ratio between the distance from the distal radius to the most distal point of the third metacarpal bone and scaphoid index was called carpo-metacarpo-scaphoid index. It excluded the constitutional influence on the scaphoid distance. The shorter the scaphoid distance, the bigger the carpo-metacarpo-scaphoid index. The average indexes were: in the control group 7.8 (+/- 0.4), in group 2A with advanced RA 21.1 (+/- 4.1), and in group 2B with early RA without bone changes 12.0 (+/- 1.6). The results were statistically significant. The measurements are easy to perform and may be helpful in the early X-ray diagnosis of RA, when there are no bone erosions, or narrowing of articular spaces.

Effect of spa therapy in Tiberias on patients with rheumatoid arthritis and osteoarthritis.

Forty-one patients with rheumatoid arthritis were treated for 2 weeks at a Tiberias spa hotel. Randomized into 2 groups, Group 1 received a combination of mineral baths and mud packs, and Group 2 had tap water baths only. Both groups had a significant but temporary improvement in Ritchie index. Group 1 showed a significant improvement in grip strength. No improvement was noticed in morning stiffness, 15 meter walk time and laboratory variables of disease activity in either group. Twelve patients with osteoarthritis (OA) received 2 weeks of treatment with mineral baths and mud packs. Statistically significant improvement for a period of 6 months was noticed in night pain, pain on passive motion, tenderness on palpation and in the index of severity of OA of the knee.

Computed tomographic (CT) demonstration of calcification of the ligamenta flava of the lumbosacral spine associated with protrusion of the intervertebral disc.

Axial computed tomographic (CT) scan of the lumbosacral region was performed in 220 patients. The patient population was divided into three groups. The control group included 40 elderly patients without calcification of the ligamenta flava. The second group included 150 patients with posterior protrusion of the intervertebral discs. The third group included 30 patients with spinal stenosis. More than 80% of the patients of the second and the third group had calcification of the ligamenta flava. The diagnostic and practical importance of these findings is discussed.

Short term effects of low dose methotrexate on the acute phase reaction in patients with rheumatoid arthritis.

Sequential daily measurements of erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) were performed for one week after an I.V. injection of 7.5-13 mg methotrexate (MTX) in 18 patients with rheumatoid arthritis. Early decreases of ESR and CRP were observed. Serum CRP was more sensitive than ESR, displaying more pronounced falls from baseline to both the minimal and to the 7th day levels. Patients receiving their first dose of MTX (n = 9) exhibited a more prominent reduction of CRP levels in comparison to veteran MTX users (n = 9). The prompt response of acute phase reactants to MTX may correspond to the relatively rapid clinical effect of the drug in RA. It may also support an antiinflammatory mechanism of action of low dose MTX.

Direct coronal high resolution computed tomography of the temporomandibular joints in patients with rheumatoid arthritis.

Direct coronal high resolution computed tomography (CT) examination of the temporomandibular joints (TMJ) was performed in 40 patients with rheumatoid arthritis (RA). The patients were divided into 3 groups. Group 1 included patients with juvenile rheumatoid arthritis (JRA). Four patients of this group had disability of the TMJ associated with overgrowth of one of the mandibular condyles. This phenomenon has not yet been reported. Group 2 consisted of 10 patients with RA with clinically asymptomatic TMJ, 4 of whom had mild erosions of the condylar head seen on CT, consistent with RA. The majority of patients in Group 3, with clinically symptomatic TMJ showed CT changes of various degrees, which are discussed in this paper. Mild bone changes, not demonstrated by conventional procedures, were clearly seen by CT. Coronal view of the CT examination had advantages over other projections.

Methotrexate in rheumatoid arthritis: a prospective study in Israeli patients with immunogenetic correlations.

In a prospective open study 44 Israeli patients with rheumatoid arthritis were treated with weekly low dose methotrexate (MTX) for up to 36 months. Nine patients withdrew from the study: six because of side effects and three due to inefficacy. One patient died of septicaemia following septic arthritis. Significant improvement, graded by Ritchie articular index, grip strength, physician's global assessment, erythrocyte sedimentation rate (ESR), and platelet counts, was noticed in response to treatment. Seronegative patients had a better clinical response. Transient gastrointestinal symptoms were common and correlated with increases of serum aspartate transaminase (AST). HLA-DR1 and DR7 were significantly associated with increased serum AST concentrations.

Computed tomographic demonstration of calcification of the ligamenta flava of the lumbosacral spine in ankylosing spondylitis.

An axial computed tomographic (CT) scan of the lumbosacral regions was performed in 65 patients. The patient population was divided into two groups. The first (control) group included 40 elderly patients without calcification of the ligamenta flava. The second group included 25 patients with ankylosing spondylitis. More than 90% of those in the second group showed calcified lumbosacral ligamenta flava. In two patients these calcifications produced spinal stenosis. The diagnostic and practical importance of these findings are discussed.

Prolonged volume depletion imitating end-stage renal failure.

Four patients with chronic renal insufficiency were erroneously diagnosed as reaching the "end stage" of their disease. All of them had had insidious salt and water depletion prolonged over a period of 5 to 8 weeks. The correct diagnosis was missed because the signs and symptoms of slowly developing volume depletion were indistinguishable from the clinical picture of terminal uremia. Correction of the salt and water depletion was followed by marked clinical improvement and return of renal function to baseline values. Postural hypotension and hyponatremia are important clues for the diagnosis of insidiously developing mild or moderate volume depletion super-imposed on chronic renal insufficiency.