Type 1 Plasminogen Deficiency With Pulmonary Involvement: Novel Treatment and Novel Mutation.

Type 1 plasminogen deficiency is a rare genetic disorder. Type 1 plasminogen deficiency is characterized by fibrin-rich pseudomembrane formation on mucosal surfaces, particularly the conjunctiva. Tracheobronchial tree involvement is a less common reported manifestation of type 1 plasminogen deficiency. Pseudomembranes in the tracheobronchial tree may result in respiratory compromise and ultimately fail if not recognized and treated. Currently, there is no specific replacement therapy approved for the treatment of congenital plasminogen deficiency. In the present paper, we report that type 1 plasminogen deficiency with novel frameshift mutation and pulmonary involvement was treated initially with systemic fresh frozen plasma followed by pulmonary lavage with fresh frozen plasma and tissue plasminogen activator.

Treatment of plasminogen deficiency patients with fresh frozen plasma.

Congenital plasminogen (Plg) deficiency leads to the development of ligneous membranes on mucosal surfaces. Here, we report our experience with local and intravenous fresh frozen plasma (FFP). We retrospectively reviewed medical files of 17 patients and their eight first-degree relatives. Conjunctivitis was the main complaint. Thirteen patients were treated both with intravenous and conjunctival FFP. Venous thrombosis did not develop in any. Genetic evaluation revealed heterogeneous mutations as well as polymorphisms. Diagnosis and treatment of Plg deficiency is challenging; topical and intravenous FFP may be an alternative treatment.

Beyond hemostasis: the challenge of treating plasminogen deficiency. A report of three cases.

Congenital plasminogen deficiency is a rare autosomal recessive disorder, characterized by chronic mucosal membranous lesions. Although the most common clinical manifestation is eye involvement as ligneous conjunctivitis, extra-ocular lesions affecting other mucosal surfaces indicates a systemic disease. In this report we describe two cases with atypical extra-ocular involvement that includes pericarditis and recurrent hematocolpos, and one with paradoxical correlation between ocular lesions and plasminogen levels. In ligneous conjunctivitis, although different treatment strategies have been tried with mild success, the only effective therapy is topical or systemic plasminogen concentrates that are not commercially available. Unfortunately there is not either effective management for cases with multisystemic disease. Hence, treatment for plasminogen deficiency is still a challenge and the variability of the clinical spectrum in this pathology makes necessary a multidisciplinary approach.

Effects of azithromycin on gene expression profiles of proinflammatory and anti-inflammatory mediators in the eyelid margin and conjunctiva of patients with meibomian gland disease.

IMPORTANCE: Topical application of azithromycin suppresses expression of proinflammatory mediators while restoring transforming growth factor ß1 (TGF-ß1) levels as evaluated by eyelid margin and conjunctival impression cytology. OBJECTIVE: To explore the effects of azithromycin therapy on expression of proinflammatory and anti-inflammatory mediators in meibomian gland disease (MGD). DESIGN, SETTING, AND PARTICIPANTS: Case-control study performed in a clinic setting from August 17, 2010, to December 31, 2010. Sixteen patients with posterior blepharitis and conjunctival inflammation due to MGD were treated with azithromycin, 1%, drops for 4 weeks. Impression cytology of the lower eyelid margin and tarsal conjunctiva to measure cytokine expression by quantitative real-time polymerase chain reaction as well as tear collection to measure matrix metalloproteinase 9 (MMP-9) activity were performed once in 8 asymptomatic healthy control participants and 5 times in the 16 symptomatic patients (every 2 weeks for 8 weeks), before, during, and after azithromycin treatment. EXPOSURE: Azithromycin, 1%, drops for 4 weeks. MAIN OUTCOMES AND MEASURES: Cytokine expression in the eyelid margin and conjunctiva, and MMP-9 activity in tears. RESULTS: Compared with a 1-time measurement of 8 healthy participants, among 16 symptomatic patients, the mean (SD; 95% CI) fold change of expression of proinflammatory mediators interleukin 1ß (IL-1ß), IL-8, and MMP-9 increased to 13.26 (4.33; 11.14-15.38; P < .001), 9.38 (3.37; 7.73-11.03; P < .001), and 13.49 (4.92; 11.08-15.90; P < .001), respectively, in conjunctival cells and to 11.75 (3.96; 9.81-13.69; P < .001), 9.31 (3.28; 7.70-10.92; P < .001), and 11.52 (3.50; 9.81-13.24; P < .001), respectively, in the eyelid margin of patients with MGD. In contrast, the mean (SD; 96% CI) fold change of expression of TGF-ß1 messenger RNA (mRNA) decreased to 0.58 (0.25; 0.46-0.70; P = .02) and 0.63 (0.14; 0.56-0.70; P = .02) in conjunctival and eyelid margin cells, respectively, of patients with MGD. Azithromycin, 1%, caused a change in the expression pattern of these mediators toward normal levels during 4 weeks of treatment. Levels of IL-1ß, IL-8, and MMP-9 mRNA remained suppressed, although they rebounded toward pretreatment values 4 weeks after azithromycin withdrawal. Expression of TGF-ß1 increased during treatment and remained at levels similar to the healthy controls after drug withdrawal. Change in tear MMP-9 activity was similar to the pattern of MMP-9 transcripts. CONCLUSIONS AND RELEVANCE: While the study did not control for potential confounding factors over time independent of the intervention that may have contributed to the results, topical azithromycin suppressed expression of proinflammatory mediators and increased expression of TGF-ß1 to normal levels. Increased TGF-ß1 expression may contribute to the anti-inflammatory activity of azithromycin in MGD.

The first two Japanese cases of severe type I congenital plasminogen deficiency with ligneous conjunctivitis: successful treatment with direct thrombin inhibitor and fresh plasma.

A 71-year-old woman and her elder sister developed ligneous conjunctivitis after ocular surgery. Laboratory tests demonstrated that the proband and her sister had 6.6% and 8.1% of plasminogen activity, and 1.2 and 1.4 mg/dl of antigen, respectively. Thus, they were diagnosed as having severe type I plasminogen deficiency, for the first time, in Japan. DNA sequencing and PCR-RFLP analyses revealed that these two cases are homozygotes of a novel A-to-G mutation at the obligatory splicing acceptor site in intron-C. Both cases were satisfactorily treated with a direct thrombin inhibitor, topical Argatroban, and topical plasma obtained from their healthy family members.

TNF receptor-associated periodic syndrome (TRAPS): description of a novel TNFRSF1A mutation and response to etanercept.

TRAPS is the most common of the autosomal dominant periodic fever syndromes. It is caused by mutations in the TNFRSF1A gene, which encodes for the type 1 TNF-receptor (TNFR1). We describe here a Brazilian patient with TRAPS associated to a novel TNFRSF1A de novo mutation and the response to anti-TNF therapy. The patient is a 9-year-old girl with recurrent fevers since the age of 3 years, usually lasting 3 to 7 days, and recurring every other week. These episodes are associated with mild abdominal pain, nausea, vomiting and generalized myalgia. Recurrent conjunctivitis and erysipela-like skin lesions in the lower limbs also occur. Laboratory studies show persistent normocytic normochromic anemia, thrombocytosis, elevated erythrocyte sedimentation rate and C-reactive protein. IgD levels are normal. Mutational screening of TNFRSF1A revealed the association of a novel C30F mutation with the common R92Q low-penetrance mutation. The R92Q mutation is seen in 5% of the general population and is associated with an atypical inflammatory phenotype. The patient had a very good response to etanercept, with cessation of fever and normalization of inflammatory markers. Our report expands the spectrum of TNFRSF1A mutations associated with TRAPS, adding further evidence for possible additive effects of a low-penetration R92Q and cysteine residue mutations, and confirms etanercept as an efficacious treatment alternative.

Anakinra improves sensory deafness in a Japanese patient with Muckle-Wells syndrome, possibly by inhibiting the cryopyrin inflammasome.

Muckle-Wells syndrome (MWS) is a dominantly inherited autoinflammatory syndrome. Patients with MWS have a mutation in CIAS1, the gene encoding cryopyrin, a component of the inflammasome that regulates the processing of interleukin-1beta (IL-1beta). In this report we describe an 8-year-old Japanese girl with MWS who had symptoms of periodic fever, urticarial rash, conjunctivitis, arthropathy, and sensory deafness. Laboratory analysis of the patient's serum showed abnormally high concentrations of C-reactive protein, serum amyloid A, and IL-1beta, and she had a heterozygous mutation in the CIAS1 gene, with C-to-T transversion at nucleotide position 778, encoding an arginine-to-tryptophan mutation at position 260 (R260W). Mononuclear cells (MNCs) isolated from the patient secreted large amounts of IL-1beta, without stimulation, and were highly sensitive to muramyldipeptide and lipopolysaccharide. After treatment with anakinra, laboratory results normalized, and clinical symptoms, including sensory deafness, disappeared, while MNCs appeared to remain activated. Thus, our case suggests that anakinra possibly affects the cryopyrin inflammasome and markedly improves the clinical and laboratory manifestations of MWS.

New CIAS1 mutation and anakinra efficacy in overlapping of Muckle-Wells and familial cold autoinflammatory syndromes.

OBJECTIVES: Muckle-Wells syndrome (MWS) and familial cold autoinflammatory syndrome (FCAS) are rare periodic fevers associated with CIAS1 mutations. A third entity, the chronic infantile neurological, cutaneous, articular (CINCA) syndrome was also recently associated with mutation in the same gene. A phenotypic and genotypic continuum seems to exist from the most benign (FCAS) to the most severe forms (CINCA). Although a CIAS1 mutation can be associated with two different phenotypes. METHODS: We report a family of three patients exhibiting the MWS and FCAS phenotypes. These phenotypes were associated with a novel missense mutation in CIAS1. RESULTS: Anakinra controlled inflammatory flares in the three patients. CONCLUSIONS: FCAS, MWS and CINCA could be different phenotype expressions of the same disease.

Ligneous conjunctivitis: a clinicopathological, immunohistochemical, and genetic study including the treatment of two sisters with multiorgan involvement.

Ligneous conjunctivitis (LC) is a rare disease characterized by wood-like pseudomembranes developing on the ocular and extraocular mucosae secondary to plasminogen (PLG) deficiency. In this paper, we report two cases of LC in two sisters of 57 and 62 years of age that presented with recurrent, bilateral pseudomembranes on conjunctiva and a history of consanguinity and deafness. Pseudomembranes showed superficial and/or subepithelial deposits of eosinophilic amorphous hyaline, amyloid-like material with a variable proportion of granulation tissue, and inflammatory cells. The eosinophilic deposits were negative for Congo red stain, immunoreactive for fibrinogen, and consistently negative for amyloid A component, transthyretin, beta(2)-microglobulin, albumin, fibronectin, collagen type IV, vimentin, and cytokeratins. Among inflammatory cells, a percentage of positivity of roughly 60% for lymphocytes T (CD3+) and 40% for lymphocytes B (CD8+), with a relation of cytotoxic/helper (CD8/4) T cells of 3:2, was found. In one case, nasal polyps and recurrent gastric peptic ulcer were also characterized by the same subepithelial hyaline deposits. A novel homozygous point mutation c.1856 C>T was found in exon 15 of the PLG gene in both patients. Amniotic membrane transplantation was done in one case with promising results.

Successful treatment of renal amyloidosis due to familial cold autoinflammatory syndrome using an interleukin 1 receptor antagonist.

Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterized by episodic fever, arthralgias, conjunctivitis, and rash triggered by cold exposure. FCAS is rarely associated with progressive renal insufficiency caused by renal amyloidosis. The genetic defect in patients with this disorder is caused by a mutation in the gene encoding the protein cryopyrin, leading to uninhibited activation of systemic inflammation through specific cellular signaling with increased production of a number of key cytokines, including interleukin 1. We describe the successful treatment of a patient with renal amyloidosis caused by FCAS by using a novel interleukin 1-receptor antagonist. Use of specific anticytokine therapy may be a new paradigm in the treatment of patients with renal amyloidosis caused by systemic inflammatory diseases.

[Successful treatment of clinical manifestations of Muckle-Wells syndrome with anakinra]. / Erfolgreiche Behandlung der klinischen Manifestationen des Muckle-Wells-Syndroms mit Anakinra.

HISTORY: A 58-year-old woman and her 18-year-old daughter were first seen in our rheumatology centre after having experienced many years of periodic fever, arthralgia and urticaria. Some months ago a diagnosis of Muckle-Wells syndrome (MWS) had been made and confirmed by genetic testing. The mother had developed partial deafness and substantial loss of vision. Her daughter had been suffering mainly from urticaria and fever at least once daily. THERAPY: Because of the established role of interleukin (IL)-1 in this hereditary disease and some positive case reports, we decided to treat these patients with the IL-1 receptor antagonist anakinra. The patients reported a great success of this treatment with virtually complete absence of any acute MWS-associated symptoms. CONCLUSION: Therapy of MWS with anakinra seems to be highly efficacious for several clinical manifestations of this disease, including laboratory markers for inflammation. It is possible that organ destruction may be prevented by this medication.

Genetic background determines susceptibility to experimental immune-mediated blepharoconjunctivitis: comparison of Balb/c and C57BL/6 mice.

Balb/c and C57BL/6 mice have been reported to be biased towards Th2 and Th1 immune responses, respectively. We investigated which strain is more susceptible to the development of experimental immune-mediated blepharoconjunctivitis (EC), which is predominantly mediated by Th2 immune responses. EC was induced by three different methods in Balb/c and C57BL/6 mice using ragweed (RW) as the antigen. The mice were thus either actively immunized with RW, passively immunized by transfer of RW-primed T cells, or passively immunized by transfer of RW-specific IgE, followed by RW challenge in eye drops. Twenty-four hours after the challenge, conjunctivas, sera and spleens were harvested for histological analysis, measurement of serum IgE and assessment of cellular immune responses, respectively. The responses of the Balb/c and C57BL/6 mice were compared. In addition, to assess the involvement of IFN-gamma in the development of EC in the two strains, IFN-gamma knockout (GKO) mice of the two strains were actively immunized and evaluated as above. Regardless of the method of induction, EC, as determined by the degree of eosinophil infiltration into the conjunctiva, was more severe in Balb/c mice than in C57BL/6 mice. Moreover, more IgE was produced by actively immunized Balb/c mice than C57BL/6 mice and RW-primed splenocytes from Balb/c mice produced more IL-4 but less IFN-gamma than those from C57BL/6 mice. EC could be induced in the GKO mice of both strains. However, when their EC was compared to that in WT mice, significantly less infiltration of eosinophils was noted in the Balb/c GKO mice. Taken together, Balb/c mice are more susceptible to EC than C57BL/6 mice and this higher susceptibility might be related to the Th2 immune response bias of Balb/c mice. Furthermore, the involvement of endogenous IFN-gamma in the development of EC in these two strains differs.

Contraceptive pills induce an improvement in congenital hypoplasminogenemia in two unrelated patients with ligneous conjunctivitis.

Severe type I plasminogen deficiency is the underlying cause of ligneous conjunctivitis, a rare disease characterized by wood-like pseudomembranes developing on the ocular and extraocular mucosa. Two unrelated female patients with ligneous conjunctivitis and moderate hypoplasminogenemia are described. Being of fertile age, they were treated with oral contraceptives, which determined a marked increase in plasminogen levels. Moreover, a palpebral pseudomembrane stopped growing in one patient and disappeared completely in the other while on the estroprogestinic treatment. In patient n. 2, who also suffered from von Willebrand's disease, prior Cushing's disease induced an increase in both von Willebrand factor and plasminogen levels, which dropped after curative hypophysectomy. Genetic plasminogen study showed a 19Lys>Glu mutation in a heterozygous state in the first proposita and in a homozygous state in the second proband. In addition, both index patients were homozygous for a new intron F-14T>G mutation, which was found to reduce the acceptor splicing site prediction score. In conclusion, oral contraceptive therapy may improve plasminogen deficiency and deserves attention as an alternative therapeutic approach in selected cases of ligneous conjunctivitis with low, but not absent, plasminogen synthesis.

Effective treatment of ligneous conjunctivitis with topical plasminogen.

PURPOSE: The etiology of ligneous conjunctivitis is now known to be due to an underlying type 1 plasminogen deficiency. We hereby report the clinical features of three cases and their response to topically administered plasminogen. DESIGN: Observational case series. METHODS: Two Caucasian females aged 5 years and an 18-month male of north African descent presented with a membranous conjunctivitis, which recurred after surgical excision. Case 1 presented before the association with plasminogen deficiency was known with a bilateral chronic membranous mucopurulent conjunctivitis from the age of 14 months associated with bronchiolitis and gingival hyperplasia. A diagnosis of ligneous conjunctivitis was entertained and a number of drops were instituted. At the age of 4 years plasminogen levels were ordered. Case 2 presented at the age of 4 years with a unilateral chronic membranous conjunctivitis. Plasminogen levels were requested as soon as a diagnosis of ligneous conjunctivitis was suspected. Case 3 was born with congenital hydrocephalus. Conjunctivitis was treated with antibiotics from the age of 1 month. He presented to the eye clinic at the age of 5 months when a clinical diagnosis of ligneous conjunctivitis was entertained and treated with a number of medications. Plasminogen levels were available at 9 months of age. RESULTS: The two female patients returned plasminogen levels of 0.25 U/ml and 0.3 U/ml, well below the normal level of 0.7-1.0 U/ml. Functional plasminogen levels in the male infant were not recordable with plasminogen antigen levels of 0.125 U/ml (normal range, 0.52-1.82). All cases have responded well to excision of the membranes and institution of topical plasminogen drops. There has been no recurrence with more than 12 months' follow-up. CONCLUSIONS: With the knowledge of the etiology of ligneous conjunctivitis, efforts are underway to identify the best method of delivery of plasminogen. Topical plasminogen concentrate from fresh frozen plasma holds promise as the definitive treatment for this chronic membranous conjunctivitis