Candido Juarez

Long-lasting treatment effect of rituximab in MuSK myasthenia.

Objective: Rituximab has emerged as an efficacious option for drug-resistant myasthenia gravis (MG). However, reports published only describe the short-term follow-up of patients treated and little is known about their long-term clinical and immunologic evolution. Our objective was to report the clinical and immunologic long-term follow-up of 17 patients (6 MuSK+MG and 11 AChR+MG) and compare the response between AChR+MG and MuSK+MG patients. Methods: Myasthenia Gravis Foundation America postintervention status and changes in treatment and antibody titers were periodically determined. Lymphocyte subpopulations, total immunoglobulin, immunoglobulin G (IgG) anti-MuSK subclasses, and anti-tetanus toxoid IgG before and after treatment were also studied. Results: After a mean post-treatment period of 31 months, 10 of the AChR+MG patients improved but 6 of them needed reinfusions. In contrast, all MuSK+MG patients achieved a remission (4/6) or minimal manifestations (2/6) status and no reinfusions were needed. Consequently, in the MuSK+MG group, prednisone doses were significantly reduced and concomitant immunosuppressants could be withdrawn. Clinical improvement was associated with a significant decrease in the antibody titers only in the 6 MuSK+MG patients. At last follow-up MuSK antibodies were negative in 3 of these patients and showed a decrease of over 80% in the other 3. Conclusion: In view of the long-lasting benefit observed in MuSK+MG patients, we recommend to use rituximab as an early therapeutic option in this group of patients with MG if they do not respond to prednisone. Classification of evidence: This study provides Class IV evidence that IV rituximab improves the clinical and immunologic status of patients with MuSK+MG.

Sustained response to Rituximab in anti-AChR and anti-MuSK positive Myasthenia Gravis patients.

We report the results of treatment with Rituximab in six severe, non-responder MG patients. We treated three AChR+MG and three MuSK+MG patients, representing 2% and 20% of the respective groups of our series. Patients were assessed according to the Myasthenia Gravis Foundation of America (MGFA) recommendations. Antibody titers to AChR and MuSK, Ig levels, and IgG subclasses, were tested before treatment and during a follow-up of 9-22 months. All patients, one class V and five class IVB, improved dramatically, with no side effects. Antibody titers declined in all patients (p=0.006). The decline was significantly better in MuSK+MG patients at 9 months (p=0.046) and correlated with a more sustained clinical improvement. We did not find any significant changes in IgG4 that could explain the different outcome observed between these two groups.

Chronic neuropathy with IgM anti-ganglioside antibodies: Lack of long term response to rituximab

Two patients with chronic motor neuropathy, high antiganglioside antibody (AGA) titers, and a declining response to IV immunoglobulins were treated with rituximab at a standard dose. The drug was well tolerated and effectively eliminated peripheral B cells (CD20+), but AGA titers continued significantly high. No clinical improvement was detected during the 1-year follow-up.

Associations between Fc gamma receptor IIA polymorphisms and the risk and prognosis of meningococcal disease

BACKGROUND In vitro studies have shown that the neutrophil Fc gamma receptor IIA (FcgammaRIIA) polymorphism influences the phagocytic capacity of neutrophils and the removal of encapsulated bacteria from the bloodstream. In particular, the R/R131 allotype is associated with less phagocytic activity. SUBJECTS AND METHODS We performed a case-control study to determine the influence of the FcgammaRIIA polymorphism (R/R131, R/H131, H/H131) on the risk and outcome of meningococcal disease. The polymorphisms were measured in 130 patients with microbiologically proven meningococcal disease diagnosed from 1987 to 1998 (cases) and 260 asymptomatic sex-matched blood donors (controls). Clinical manifestations and complications of meningococcal disease were recorded, and a prognostic score (based on age, hemorrhagic diathesis, neurologic signs, and the absence of preadmission antibiotic) therapy was calculated. RESULTS The distributions of FcgammaRIIA allotypes were similar in cases and controls. However, among patients with meningococcal infection, fulminant meningococcal disease (odds ratio [OR] = 3.9; 95% confidence interval [CI]: 1.0 to 16; P = 0.04) and meningococcemia without meningitis (OR = 3.0; 95% CI: 1.4 to 7.8; P = 0.004) were more common in those with the FcgammaRIIA-R/R131 allotype. Complications were also significantly more frequent in these patients. Of the 42 patients with the R/R131 allotype, 31 (74%) had an adverse prognostic score, compared with 7% (4 of 59) of those with the R/H131 allotype and 3% (1 of 29) of those with the H/H131 allotype (P <0.0001). CONCLUSION The FcgammaRIIA-R/R131 allotype is associated with more severe forms of meningococcal disease.

Anti-MDA5 antibodies in a large Mediterranean population of adults with dermatomyositis.

A new myositis-specific autoantibody directed against melanoma differentiation-associated gene 5 (anti-MDA5) has been described in patients with dermatomyositis (DM). We report the clinical characteristics of patients with anti-MDA5 in a large Mediterranean cohort of DM patients from a single center, and analyze the feasibility of detecting this autoantibody in patient sera using new assays with commercially available recombinant MDA5. The study included 117 white adult patients with DM, 15 (13%) of them classified as clinically amyopathic dermatomyositis (CADM). Clinical manifestations were analyzed, with special focus on interstitial lung disease and its severity. Determination of anti-MDA5 antibodies was performed by a new ELISA and immunoblot technique. In sera, from 14 (12%) DM patients (8 CADM), MDA5 was recognized by ELISA, and confirmed by immunoblot. Eight of the 14 anti-MDA5-positive patients (57.14%) presented rapidly-progressive interstitial lung disease (RP-ILD) versus 3 of 103 anti-MDA5-negative patients (2.91%) (P < 0.05; OR: 44.4, 95% CI 9.3–212). The cumulative survival rate was significantly lower in anti-MDA5-positive patients than in the remainder of the series (P < 0.05). Patients with anti-MDA5-associated ILD presented significantly lower 70-month cumulative survival than antisynthetase-associated ILD patients. Among the cutaneous manifestations, only panniculitis was significantly associated with the presence of anti-MDA5 antibodies (P < 0.05; OR: 3.85, 95% CI 1.11–13.27). These findings support the reliability of using commercially available recombinant MDA5 for detecting anti-MDA5 antibodies and confirm the association of these antibodies with RP-ILD in a large series of Mediterranean patients with DM.

Identification of protein components reactive with anti-PM/Scl autoantibodies.

The PM/Scl antigen from mammalian cells has been characterized as a nucleolar and nucleoplasmic molecular complex containing at least 16 polypeptides ranging in molecular weight from 110 to 20 kD. Of these polypeptides. we have found those of68, 39 and 20 kD to be in a phosphorilated form. Whereas the entire complex was precipitated by all the anti‐PM/Scl sera tested, in immunoblots the antibodies specifically recognized determinants on the 110‐kD protein. This protein was immunoprecipitated more preferentially from nuclcoli extracts than from total cell extracts. Moreover, this protein disappeared from the immunoprecipitates when treated with DNAse. Likewise, the immunoblol reaction of the specific antibodies with the 110‐kD protein was abolished by treatment of the extracts with DNAse and trypsin, and was resistant when extracts were treated with RNAsc. Affinity‐purified antibodies from this protein selectively stained the nucleoli and the nucleoplasm of the mammalian cells. Moreover, when the cultured cells used in immunofluorescence were treated with DNAse, the affinity purified antibodies from the 110‐kD protein gave negative fluorescence. However, when whole anti‐PM/Scl sera were used, a nucleolar and nucleoplasmic staining was found. We conclude that the 110‐kD protein has at least one of the autoimmunogenic epilopes of the PM/Sel antigen, recognized by all anti‐PM/Scl sera tested. Other epitopes differing in their DNAse sensitivity may also be present in the PM/Scl antigen.

Antibodies to AChR, MuSK and VGKC in a patient with myasthenia gravis and Morvan's syndrome

Background A 46-year-old woman presented to a local hospital with acute respiratory failure and a 2-year progressive history of fatigue, personality changes, increased sweating, dysphagia with substantial weight loss, dysarthria, and intermittent ptosis and diplopia. Neurological examination showed facial weakness, lingual atrophy and bulbar palsy, which necessitated the use of a feeding tube and ventilatory support. Mild limb weakness with severe muscle atrophy and diffuse muscle twitches were observed. The patient had also developed visual hallucinations and persecutory delusions. Her personal and family medical histories were unremarkable.Investigations Sensory and motor nerve conduction studies, repetitive nerve stimulation, electromyogram, blood-cell counts, general chemistry and metabolic function tests, a CT scan, an [18F]fluorodeoxyglucose-PET scan, and tests for serum antibodies to acetylcholine receptors, muscle-specific tyrosine kinase, voltage-gated potassium channels, P/Q-type voltage-gated calcium channels, and paraneoplastic antigens, were carried out.Diagnosis Myasthenia gravis associated with antibodies to acetylcholine receptor and muscle-specific tyrosine kinase, and Morvans syndrome associated with antibodies to voltage-gated potassium channels in the absence of thymoma.Management Combined treatment with prednisone, intravenous immunoglobulin, ciclosporin, and rituximab.

Relevance of genetically determined host factors to the prognosis of meningococcal disease

To assess the relevance of genetically determined host factors for the prognosis of meningococcal disease, Fc gamma receptor IIA (FcγRIIA), the tumor necrosis factor alpha (TNF-α) gene promoter region, and plasminogen-activator-inhibitor-1 (PAI-1) gene polymorphisms were studied in 145 patients with meningococcal disease and in 290 healthy controls matched by sex. Distribution of FcγRIIA, TNF-α, and PAI-1 alleles was not significantly different between patients and controls. Patients with the FcγRIIA-R/R 131 allotype scored ≥1 point in the Barcelona prognostic system more frequently than patients with other allotypes (odds ratio, 18.6; 95% confidence interval, 7.1–49.0, P<0.0001), and they had a higher risk of sequelae (odds ratio, 3.5; 95% confidence interval, 1.1–11.7; P=0.03). Fc gamma receptor IIA polymorphism was associated with markers of disease severity, but TNF-α and PAI-1 polymorphisms were not.

Role of the STAT1 pathway in apoptosis induced by fludarabine and JAK kinase inhibitors in B-cell chronic lymphocytic leukemia

Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors that have been implicated in tumoral transformation, especially in hematological malignancies. Because of this, the JAK/STAT pathway is attractive as a therapeutic target in these tumors. In the present study, we analyzed the ability of fludarabine and two JAK kinase inhibitors, AG490 and WHI-P131, to block STAT1 activation and induce apoptosis on B-cell chronic lymphocytic leukemia (B-CLL) cells. All drugs were able to induce a high percentage of apoptosis on B-CLL cells from all patients studied. However, only AG490 and WHI-P131 were able to strongly suppress the STAT1 activation of B-CLL cells. In conclusion, our data show that JAK kinase inhibitors, such as AG490 and WHI-P131 are able to inhibit the STAT1 pathway on B-CLL cells and are strong inductors of apoptosis on these cells.

VSL#3 probiotic treatment decreases bacterial translocation in rats with carbon tetrachloride-induced cirrhosis

Probiotics can prevent pathological bacterial translocation in cirrhosis by modulating intestinal microbiota and improving gut barrier and immune disturbances. To evaluate the effect of probiotic VSL#3 on bacterial translocation, intestinal microbiota, gut barrier and inflammatory response in rats with experimental cirrhosis.