A naturally occurring mutation in the ectodomain of the TSH receptor (TSHr), K183R, has been described recently in a familial case of gestational hyperthyroidism. Hyperthyroidism was explained by the widening of the specificity of the mutant receptor toward human CG (hCG). In the present study, we attempted to understand in molecular terms the structure-phenotype relationships of this mutant in light of the available structural model of TSHr ectodomain established on the template of the atomic structure of the porcine ribonuclease inhibitor. To this aim, we studied by site-directed mutagenesis and functional assays in transfected COS cells the effects of substituting amino acids with different physicochemical properties for lysine 183. Unexpectedly, all TSHr mutants displayed widening of their specificity toward hCG. Molecular dynamics simulations suggested that the gain of function would be secondary to the release of a nearby glutamate residue (E157) from a salt bridge with K183. This hypothesis was supported by further site-directed mutagenesis experiments showing that the presence of an acidic residue in position 157, or in its vicinity, was required to observe the increase in sensitivity to hCG (an acidic residue in position 183 can partially fulfill the role of a free acidic residue in position 157 when tested on the background of a E157A mutant). Our results suggest also that additional natural mutations (especially K183M, N, or Q) in position 183 of TSHr are expected to be found in gestational hyperthyroidism.
PurposeTo analyze the effect of tumor necrosis factor inhibitor therapy on ocular relapses in patients with Susac syndrome.MethodsMulticenter retrospective case series of patients with ocular Susac syndrome treated with a TNF inhibitor (either infliximab or adalimumab). Diagnosis was based on neurologic, ophthalmic, otologic, biologic and imaging typical findings.ResultsFive patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. In 4 of the 5 patients a TNF‐inhibitor (3 infliximab and 2 adalimumab) was started due to treatment failure. In these patients cortisone could not be decreased below a daily dose of 10 mg without the occurrence of relapses (with an average of 4.25 relapses over a mean follow‐up of 330 days) despite the use of a mean of 2.75 different immunosuppressive drugs. After introduction of an anti‐TNF agent the daily cortisone dose could successfully be tapered below 10 mg in all patients with a complete stop in 3 patients, with a mean number of 1.25 relapses during a mean follow‐up of 1,199 days. In the fifth patient, disease activity was well controlled with only steroid sparing immunosuppressive agents and only 1 relapse during approximately 5 years of follow up until these had to be stopped for a desired pregnancy. No relapse was documented during 60 weeks of follow‐up while on infliximab treatment afterwards.ConclusionsAnti‐TNF antibodies can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to conventional immunosuppressive treatment.
Purpose: To evaluate the effect of tumor necrosis factor (TNF) inhibitor therapy on ocular relapses in patients with Susac syndrome. Methods: Multicenter retrospective cohort study of patients diagnosed with Susac syndrome according to classical clinical criteria. We evaluated the disease activity before and after introduction of anti-TNF therapy and its value as a steroid-sparing agent. Results: Five patients were included. All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients, and adalimumab was started in two patients. Patients had on average 5 ocular relapses during a mean follow-up time of 2.59 years before introducing a TNF inhibitor, corresponding with on average 1.93 relapses per year. After the introduction of an anti-TNF agent, this number was reduced by factor 5.51 to an average of 0.35 relapses per year for a mean follow-up of 2.86 years (P = 0.10). Before anti-TNF introduction ocular relapses occurred at a mean daily dose of 34 mg of prednisone, whereas with anti-TNF treatment, corticosteroid administration could be completely stopped in four patients with one patient still needing 5 mg daily (P = 0.10). Infliximab and adalimumab generally were well tolerated, and no serious adverse events were reported. Conclusion: Although not statistically significant, our results suggest that anti-TNF therapy can be a valuable option for the treatment of ocular Susac syndrome and may especially be considered in those patients unresponsive to more conventional immunosuppressive treatment.
We report the case of a 57-year-old man, presenting with bilateral panuveitis, bilateral sacroiliitis, intermittent pyrexia and a pulmonary nodule. The patient had been under immunosuppressive treatment for 2 years for Behçet's disease. However, he did not fulfill the diagnostic criteria of Behçet's disease. Blood analysis showed a very high C reactive protein (CRP at 34 mg/dl). In view of severe intra-ocular inflammation, the anterior chamber was punctured. Polymerase chain reaction (PCR) on the aqueous humour and on the blood revealed the presence of Tropheryma whippelii DNA, an agent responsible for Whipple's disease. The patient was treated with ceftriaxone followed by trimethoprim-sulfamethoxazol for 1 year with good clinical and biological evolution. This case illustrates the difficulty to diagnose an atypical Whipple's disease. In cases of uveitis with atypical signs and/or not responding to the treatment, the internist must consider to perform an analysis of the ocular fluids.
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