Simon Carette

EPIDURAL CORTICOSTEROID INJECTIONS FOR SCIATICA DUE TO HERNIATED NUCLEUS PULPOSUS

BACKGROUND Although epidural corticosteroid injections are commonly used for sciatica, their efficacy has not been established. METHODS In a randomized, double-blind trial, we administered up to three epidural injections of methylprednisolone acetate (80 mg in 8 ml of isotonic saline) or isotonic saline (1 ml) to 158 patients with sciatica due to a herniated nucleus pulposus. All patients had Oswestry disability scores higher than 20 (on a scale of 1 to 100, with scores of 20 or less indicating minimal disability, and higher scores greater disability). RESULTS At three weeks, the Oswestry score had improved by a mean of -8.0 in the methylprednisolone group and -5.5 in the placebo group (95 percent confidence interval for the difference, -7.1 to 2.2). Differences in improvements between the groups were not significant, except for improvements in the finger-to-floor distance (P=0.006) and sensory deficits (P=0.03), which were greater in the methylprednisolone group. After six weeks, the only significant difference was the improvement in leg pain, which was greater in the methylprednisolone group (P=0.03). After three months, there were no significant differences between the groups. The Oswestry score had improved by a mean of -17.3 in the methylprednisolone group and -15.4 in the placebo group (95 percent confidence interval for the difference, -9.3 to 5.4). At 12 months, the cumulative probability of back surgery was 25.8 percent in the methylprednisolone group and 24.8 percent in the placebo group (P=0.90). CONCLUSIONS Although epidural injections of methylprednisolone may afford short-term improvement in leg pain and sensory deficits in patients with sciatica due to a herniated nucleus pulposus, this treatment offers no significant functional benefit, nor does it reduce the need for surgery.

A controlled trial of corticosteroid injections into facet joints for chronic low back pain.

BACKGROUND Chronic low back pain is a common problem with many treatments, few of which have been rigorously evaluated. This randomized, placebo-controlled trial was designed to evaluate the efficacy of injections of corticosteroid into facet joints to treat chronic low back pain. METHODS Patients with chronic low back pain who reported immediate relief of their pain after injections of local anesthetic into the facet joints between the fourth and fifth lumbar vertebrae and the fifth lumbar and first sacral vertebrae were randomly assigned to receive under fluoroscopic guidance injections of either methylprednisolone acetate (20 mg; n = 49) or isotonic saline (n = 48) in the same facet joints. Ninety-five patients were followed for six months and their condition assessed with scales of pain severity, back mobility, and limitation of function. RESULTS After one month, none of the outcome measures evaluating pain, functional status, and back flexion differed clinically or statistically between the two study groups. Forty-two percent of the patients who received methylprednisolone and 33 percent of those who received placebo reported marked or very marked improvement (95 percent confidence interval for the difference, -11 to 28 percentage points; P = 0.53). The results were similar after three months. At the six-month evaluation, the patients treated with methylprednisolone reported more improvement, less pain on the visual-analogue scale, and less physical disability. The differences were reduced, however, when concurrent interventions were taken into account. Moreover, only 11 patients (22 percent) in the methylprednisolone group and 5 (10 percent) in the placebo group had sustained improvement from the first month to the sixth month (95 percent confidence interval for the difference, -2 to 26; P = 0.19). CONCLUSIONS We conclude that injecting methylprednisolone acetate into the facet joints is of little value in the treatment of patients with chronic low back pain.

Distribution of arterial lesions in Takayasu's arteritis and giant cell arteritis

Objectives To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasus arteritis (TAK) and giant cell arteritis (GCA). Methods Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. Conclusions Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.

Identification of multiple genetic susceptibility loci in Takayasu arteritis

Takayasu arteritis is a rare inflammatory disease of large arteries. The etiology of Takayasu arteritis remains poorly understood, but genetic contribution to the disease pathogenesis is supported by the genetic association with HLA-B*52. We genotyped ~200,000 genetic variants in two ethnically divergent Takayasu arteritis cohorts from Turkey and North America by using a custom-designed genotyping platform (Immunochip). Additional genetic variants and the classical HLA alleles were imputed and analyzed. We identified and confirmed two independent susceptibility loci within the HLA region (r(2) < 0.2): HLA-B/MICA (rs12524487, OR = 3.29, p = 5.57 × 10(-16)) and HLA-DQB1/HLA-DRB1 (rs113452171, OR = 2.34, p = 3.74 × 10(-9); and rs189754752, OR = 2.47, p = 4.22 × 10(-9)). In addition, we identified and confirmed a genetic association between Takayasu arteritis and the FCGR2A/FCGR3A locus on chromosome 1 (rs10919543, OR = 1.81, p = 5.89 × 10(-12)). The risk allele in this locus results in increased mRNA expression of FCGR2A. We also established the genetic association between IL12B and Takayasu arteritis (rs56167332, OR = 1.54, p = 2.18 × 10(-8)).

A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Takayasu Arteritis

To compare the efficacy of abatacept to that of placebo for the treatment of giant cell arteritis (GCA).

Association of granulomatosis with polyangiitis (Wegener's) with HLA-DPB1*04 and SEMA6A gene variants: Evidence grom genome-wide analysis

OBJECTIVE To identify genetic determinants of granulomatosis with polyangiitis (Wegeners) (GPA). METHODS We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. RESULTS Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10(-50) and 2.18 × 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10(-8) ). CONCLUSION We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.

Severe, acute pulmonary disease in patients with systemic lupus erythematosus: Ten years of experience at the National Institutes of Health

The sudden development of diffuse pulmonary infiltration in a patient with SLE presents difficult diagnostic and therapeutic problems to the clinician. In the past ten years, we have seen eight patients with this problem. Neither roentgenograms nor clinical findings were specific. In six patients, pulmonary hemorrhage was found, but in only two of them did it exist alone. In the other four, heart failure, uremia, and coagulopathy complicated the findings. In one patient, P carinii was the cause; in one congestive heart failure, which was not obvious clinically or radiologically, was the cause. Three patients died: one of uncomplicated pulmonary hemorrhage, one with pulmonary hemorrhage occurring during the treatment of pneumonia due to L bozemanii, and one with pulmonary hemorrhage and multiple complications including sepsis due to Candida. On the basis of this experience, we have recommended a plan of action for physicians facing this problem.

Granulomatosis with polyangiitis (Wegener's) is associated with HLA-DPB1*04 and SEMA6A gene variants: Evidence from genome-wide analysis.

OBJECTIVE To identify genetic determinants of granulomatosis with polyangiitis (Wegeners) (GPA). METHODS We carried out a genome-wide association study (GWAS) of 492 GPA cases and 1,506 healthy controls (white subjects of European descent), followed by replication analysis of the most strongly associated signals in an independent cohort of 528 GPA cases and 1,228 controls. RESULTS Genome-wide significant associations were identified in 32 single-nucleotide polymorphic (SNP) markers across the HLA region, the majority of which were located in the HLA-DPB1 and HLA-DPA1 genes encoding the class II major histocompatibility complex (MHC) DPβ chain 1 and DPα chain 1 proteins, respectively. Peak association signals in these 2 genes, emanating from SNPs rs9277554 (for DPβ chain 1) and rs9277341 (DPα chain 1) were strongly replicated in an independent cohort (in the combined analysis of the initial cohort and the replication cohort, P = 1.92 × 10(-50) and 2.18 × 10(-39) , respectively). Imputation of classic HLA alleles and conditional analyses revealed that the SNP association signal was fully accounted for by the classic HLA-DPB1*04 allele. An independent single SNP, rs26595, near SEMA6A (the gene for semaphorin 6A) on chromosome 5, was also associated with GPA, reaching genome-wide significance in a combined analysis of the GWAS and replication cohorts (P = 2.09 × 10(-8) ). CONCLUSION We identified the SEMA6A and HLA-DP loci as significant contributors to risk for GPA, with the HLA-DPB1*04 allele almost completely accounting for the MHC association. These two associations confirm the critical role of immunogenetic factors in the development of GPA.

Trauma and Fibromyalgia: Is There an Association and What Does It Mean?

OBJECTIVES The primary objective is to review current research with respect to the role of trauma in fibromyalgia (FM). A secondary objective is to hypothesize which steps need to be taken, first to determine whether such an association truly exists, and second to clarify what such an association might mean. METHODS An extensive literature review was undertaken, including Medline from 1979 to the present. RESULTS The strongest evidence supporting an association between trauma and FM is a recently published Israeli study in which adults with neck injuries had greater than a 10-fold increased risk of developing FM within 1 year of their injury, compared with adults with lower extremity fractures (P= .001). Several other studies provide a hypothetical construct for such an association. These include studies on (1) postinjury sleep abnormalities; (2) local injury sites as a source of chronic distant regional pain; and (3) the concept of neuroplasticity. There are, however, several primary arguments against such an association: (1) FM may not be a distinct clinical entity; (2) FM may be a psychological, rather than physical, disease; (3) the evidence supporting any association is limited and not definitive; (4) the Israeli study, itself, has some methodological limitations; and (5) other factors may be more important than the injurious event in determining chronic symptoms after an acute injury. CONCLUSIONS Although there is some evidence supporting an association between trauma and FM, the evidence is not definitive. Further prospective studies are needed to confirm this association and to identify whether trauma has a causal role.

A Randomized, Double-Blind Trial of Abatacept (CTLA-4Ig) for the Treatment of Giant Cell Arteritis: ABATACEPT FOR THE TREATMENT OF GCA

To compare the efficacy of abatacept to that of placebo for the treatment of Takayasu arteritis (TAK).