An observational study of innate immune responses in patients with acute appendicitis.

Acute appendicitis is a common surgical emergency worldwide. Exaggerated immune responses could be associated with appendicitis. This study aimed at characterizing immune responses towards a large variety of gut commensals and pathogens, and pattern recognition receptor (PRR) ligands, and investigating the course of systemic inflammation in a prospective cohort of acute appendicitis patients. PBMC responses of 23 patients of the cohort and 23 healthy controls were characterized more than 8 months post-surgery. Serum cytokine levels were measured in 23 patients at the time of appendicitis and after one month. CRP, WBC and percentage of neutrophils were analyzed in the total cohort of 325 patients. No differences in PBMC responses were found between patients and controls. Stronger IL-10 responses were found following complicated appendicitis. A trend towards lower IL-8 responses was shown following gangrenous appendicitis. Serum IL-10 and IL-6 were significantly elevated at presentation, and IL-6, IL-8 and TNF-α levels were higher in complicated appendicitis. Routine biomarkers could predict severity of appendicitis with high specificities, but low sensitivities. Cytokine responses in patients following acute appendicitis did not differ from healthy controls. Higher serum cytokine levels were found in acute complicated and gangrenous cases. Further research into discriminative biomarkers is warranted.

The Efficacy, Safety and Tolerability of Canakinumab in the Treatment of Familial Mediterranean Fever: A Systematic Review of the Literature.

Familial Mediterranean Fever (FMF) is the most prevalent genetic autoinflammatory disorder. In most patients, treatment with colchicine can prevent attacks of fever and inflammation. However, 5%-10% of patients are resistant to colchicine treatment, while a similar percentage cannot tolerate colchicine in doses needed to prevent attacks. For these patients, Canakinumab, a full human antibody against IL-1ß, has been approved recently by the FDA and EMA. In this article, we present a systematic review of the long-term efficacy, safety, and tolerability of Canakinumab in FMF patients who cannot tolerate colchicine or who are resistant to colchicine treatment.

Campylobacter fetus spondylodiscitis in a patient with HIV infection and restored CD4 count.

Campylobacter fetus (C. fetus) is a rare condition and mostly seen in elderly or immunocompromised patients. We present the first case of C. fetus spondylodiscitis in a virologically suppressed HIV seropositive patient with low back pain. MRI was performed and showed spondylodiscitis of the L4-L5 region. Empirical antibiotic therapy with flucloxacillin was started after blood cultures were drawn and an image-guided disc biopsy was performed. Blood cultures remained negative. The anaerobic culture of the puncture biopsy of the disc revealed presence of C. fetus after which the antibiotic treatment was switched to ceftriaxone. Guided by the susceptibility results, the therapy was switched to ciprofloxacin orally for 6 weeks after which the patient made full clinical, biochemical and radiographic recovery. Since no other immune-deficient conditions were noted, it is important to highlight that patients with HIV infection with restored CD4 counts and complete virological suppression can still be susceptible for infections caused by rare pathogens. Low back pain should raise suspicion for these conditions and should be examined properly.

Mimickers of Urticaria: Urticarial Vasculitis and Autoinflammatory Diseases.

A wide differential diagnosis must be considered in a patient presenting with urticarial plaques. Although acute and chronic urticaria are the commonest diagnoses, other differential diagnoses include polymorphous eruption of pregnancy, mast cell disorders, hypereosinophilic syndrome, urticarial vasculitis, pemphigoid, systemic lupus erythematosus, and autoinflammatory disease. This review will specifically address urticarial vasculitis and autoinflammatory syndromes. These entities represent contrasting examples of urticarial-like lesions resulting from either an adaptive immune complex-mediated mechanism (urticarial vasculitis) or an innate immune-mediated mechanism (autoinflammatory disorders), with differing therapeutic implications. In patients presenting with painful, persistent plaques that last more than 24 hours and resolve with bruising of the skin, consideration should be given to a diagnosis of urticarial vasculitis. A biopsy should be obtained to ascertain this diagnosis. In patients presenting with a persistent history of recurrent urticarial plaques associated with signs of systemic inflammation including fevers and elevated inflammatory markers (C-reactive protein [CRP]/serum amyloid A, leukocytosis, and negative connective tissue serologies), consideration should be given to autoinflammatory disorders: the 3 cryopyrin-associated periodic syndromes, Schnitzler syndrome, and familial cold autoinflammatory syndrome 2. Serum protein electrophoresis should be checked to rule out an underlying monoclonal gammopathy.

Interleukin-1 Blockade: An Update on Emerging Indications.

Interleukin (IL)-1 is a pro-inflammatory cytokine that induces local and systemic inflammation aimed to eliminate microorganisms and tissue damage. However, an increasing number of clinical conditions have been identified in which IL-1 production is considered inappropriate and IL-1 is part of the disease etiology. In autoinflammatory diseases, gout, Schnitzler's syndrome, and adult-onset Still's disease, high levels of inappropriate IL-1 production have been shown to be a key process in the etiology of the disease. In these conditions, blocking IL-1 has proven very effective in clinical studies. In other diseases, IL-1 has shown to be present in disease process but is not the central driving force of inflammation. In these conditions, including type 1 and 2 diabetes mellitus, acute coronary syndrome, amyotrophic lateral sclerosis, and several neoplastic diseases, the benefits of IL-1 blockade are minimal or absent.

Hyperimmunoglobulin D syndrome in childhood.

Hyperimmunoglobulinemia D and periodic fever syndrome, an autoinflammatory syndrome, is caused by mutations in the gene coding for mevalonate kinase. The disease is clinically characterized by recurrent attacks of fever accompanied by an array of inflammatory symptoms including lymphadenopathy, rash, arthritis, and gastrointestinal complaints. Most patients have their first attack in the first year of life, typically after a childhood vaccination. The frequency of attacks is highest during childhood, with a gradual decrease after adolescence. Frequent fever attacks impair quality of life and the achievement of educational milestones. Recent reports show promising results with anakinra and etanercept to treat the attacks.

Long-term follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome.

The hyperimmunoglobulinemia D and periodic fever syndrome (HIDS), one of the autoinflammatory syndromes, is caused by mutations in the gene coding for mevalonate kinase (MVK). We conducted the current study to assess the genetic, laboratory, and clinical features as well as the complications and course of disease in patients with genetically confirmed HIDS. In addition, we studied the quality of life and course of life in a selection of patients. Follow-up data were obtained by a questionnaire sent to all physicians of patients in the International HIDS Database. In addition, we assessed the course of life and quality of life in Dutch patients aged >16 years using validated quality of life instruments. Data were obtained from 103 patients from 18 different countries. The median age of first attack was 6 months (range, 0-120 mo), with a median period of 9.9 years from onset of disease to diagnosis. The most frequent symptoms that accompanied attacks of fever were lymphadenopathy, abdominal pain, arthralgia, diarrhea, vomiting, skin lesions, and aphthous ulcers. Amyloidosis was a severe but infrequent complication (2.9%). The median serum IgD level was 400 U/mL. IgD levels were normal in 22% of patients. The 4 most prevalent mutations (V377I, I268T, H20P/N, P167L) accounted for 71.5% of mutations found. The frequency of attacks decreased with the patient's increasing age, although 50% of patients over the age of 20 years still had 6 or more attacks per year. Many drugs have been tried in HIDS. Some patients responded to high-dose prednisone (24.4% response). Anakinra and etanercept can also be effective (33.3% response). Quality of life was determined in a subgroup of patients (n = 28). Social functioning, general health perception, and vitality were significantly lower in patients with HIDS than in controls, as were autonomy and social development. In addition, HIDS had an adverse impact on educational achievements and employment status. In conclusion, HIDS is an early-onset disease that is accompanied by an array of inflammatory symptoms. Although the frequency of attacks decreases during the patient's life, many patients continue to have frequent attacks. HIDS impairs several aspects of quality of life.

Defective apoptosis of peripheral-blood lymphocytes in hyper-IgD and periodic fever syndrome.

Hereditary periodic fever syndromes are characterized by incapacitating attacks of fever and generalized inflammation. While the mutated genes for the major syndromes in this group are known, the pathogenesis remains unclear. The aim of this study was to investigate apoptosis in patients with periodic fever as a possible pathogenic factor. We measured anisomycin-induced apoptosis with annexin-V flow cytometry and caspase-3/7 activity in peripheral-blood lymphocytes from symptom-free patients with hyper-IgD and periodic fever syndrome (HIDS; n = 10), TNF-receptor-associated periodic syndrome (TRAPS; n = 7), and familial Mediterranean fever (FMF; n = 2). HIDS lymphocytes showed a decreased percentage of apoptosis during remission by both methods compared with controls (17.8% vs 55.4%), whereas no difference was observed in TRAPS or FMF lymphocytes. This defective apoptosis of lymphocytes may be a central pathogenic mechanism in HIDS, since dysfunction of one of the inhibitory mechanisms to curtail the immunologic response could cause an unbridled generalized inflammation after a trivial stimulus.