Kieron S. Leslie

Use of Canakinumab in the Cryopyrin-Associated Periodic Syndrome

BACKGROUND The cryopyrin-associated periodic syndrome (CAPS) is a rare inherited inflammatory disease associated with overproduction of interleukin-1. Canakinumab is a human anti-interleukin-1beta monoclonal antibody. METHODS We performed a three-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS. In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least two more doses of canakinumab. We evaluated therapeutic responses using disease-activity scores and analysis of levels of C-reactive protein (CRP) and serum amyloid A protein (SAA). RESULTS In part 1 of the study, 34 of the 35 patients (97%) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81%) receiving placebo (P<0.001). At the end of part 2, median CRP and SAA values were normal (<10 mg per liter for both measures) in patients receiving canakinumab but were elevated in those receiving placebo (P<0.001 and P=0.002, respectively). Of the 31 patients, 28 (90%) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (P=0.03). Two serious adverse events occurred during treatment with canakinumab: one case of urosepsis and an episode of vertigo. CONCLUSIONS Treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS. (ClinicalTrials.gov number, NCT00465985.)

In vivo regulation of interleukin 1β in patients with cryopyrin-associated periodic syndromes

The investigation of interleukin 1β (IL-1β) in human inflammatory diseases is hampered by the fact that it is virtually undetectable in human plasma. We demonstrate that by administering the anti–human IL-1β antibody canakinumab (ACZ885) to humans, the resulting formation of IL-1β–antibody complexes allowed the detection of in vivo–produced IL-1β. A two-compartment mathematical model was generated that predicted a constitutive production rate of 6 ng/d IL-1β in healthy subjects. In contrast, patients with cryopyrin-associated periodic syndromes (CAPS), a rare monogenetic disease driven by uncontrolled caspase-1 activity and IL-1 production, produced a mean of 31 ng/d. Treatment with canakinumab not only induced long-lasting complete clinical response but also reduced the production rate of IL-1β to normal levels within 8 wk of treatment, suggesting that IL-1β production in these patients was mainly IL-1β driven. The model further indicated that IL-1β is the only cytokine driving disease severity and duration of response to canakinumab. A correction for natural IL-1 antagonists was not required to fit the data. Together, the study allowed new insights into the production and regulation of IL-1β in man. It also indicated that CAPS is entirely mediated by IL-1β and that canakinumab treatment restores physiological IL-1β production.

Two-year results from an open-label, multicentre, phase III study evaluating the safety and efficacy of canakinumab in patients with cryopyrin-associated periodic syndrome across different severity phenotypes

Objective Longer-term effects of prolonged selective interleukin-1β blockade with canakinumab were evaluated in the largest cohort of cryopyrin-associated periodic syndrome (CAPS) patients studied to date. Methods Adult and paediatric CAPS patients (n=166, including canakinumab-naive and pretreated patients from previous studies) received canakinumab subcutaneously 150 mg or 2 mg/kg (≤40 kg) every 8 weeks for up to 2 years. Response and relapse was assessed using scores for disease activity, skin rash and C-reactive protein (CRP) and/or serum amyloid A (SAA) levels. Results Complete response was achieved in 85 of 109 canakinumab-naive patients (78%; 79/85 patients within 8 days, and five patients between days 10 and 21). Of 141 patients with an available relapse assessment, 90% did not relapse, their CRP/SAA levels normalised (<10 mg/l) by day 8, and remained in the normal range thereafter. Median treatment duration was 414 days (29–687 days). Upward adjustments of dose or frequency were needed in 24.1% patients; mostly children and those with severe CAPS. Predominant adverse events (AE) were infections (65.7%) of mostly mild-to-moderate severity. Serious AE reported in 18 patients (10.8%) were mainly infections and were responsive to standard treatment. The majority of patients (92%) reported having no injection-site reactions and only 8% patients reported mild-to-moderate reactions. Patients receiving vaccination (15%) showed normal immune response. Conclusions Subcutaneous canakinumab 150 mg every 8 weeks was well tolerated and provided substantial disease control in children and adults across all CAPS phenotypes. Higher canakinumab doses in younger patients and more severe CAPS disease were efficacious in achieving complete responses without evidence of increased AE. Trial registration number: NCT00685373 (clinicaltrials.gov)

Cryopyrin-associated periodic syndromes and autoinflammation.

Autoinflammatory syndromes are a distinct class of inherited diseases of cytokine dysregulation with important cutaneous features. Several disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome and neonatal onset multisystem inflammatory disorder (NOMID), are associated with mutations in a common gene, CIAS‐1. These disorders are now believed to represent related conditions along a spectrum of disease severity, in which FCAS is the mildest and NOMID is the most severe phenotype. Patients typically present with lifelong atypical urticaria with systemic symptoms, with potential for developing end‐organ damage due to chronic inflammation. Advances in the understanding of the genetic basis of these syndromes have also revealed cytokine signalling molecules that are critical to normal regulation of inflammatory pathways. The dramatic response of these syndromes to anakinra, an interleukin (IL)‐1 antagonist, highlights the important role of IL‐1 cytokine signalling in the pathogenesis of this rare but fascinating class of diseases.

Sustained remission of symptoms and improved health-related quality of life in patients with cryopyrin-associated periodic syndrome treated with canakinumab: results of a double-blind placebo-controlled randomized withdrawal study

IntroductionTo assess the effect of canakinumab, a fully human anti-interleukin-1β antibody, on symptoms and health-related quality of life (HRQoL) in patients with cryopyrin-associated periodic syndrome (CAPS).MethodsIn this 48-week, phase 3 study, patients with CAPS received canakinumab 150 mg subcutaneously at 8-week intervals. All patients (n = 35) received canakinumab during weeks 1 through 8; weeks 9 through 24 constituted a double-blind placebo-controlled withdrawal phase, and weeks 24 through 48 constituted an open-label phase in which all patients received canakinumab. Patient and physician assessments of symptoms, levels of inflammatory markers, and HRQoL were performed.ResultsRapid symptom remission was achieved, with 89% of patients having no or minimal disease activity on day 8. Responses were sustained in patients receiving 8-weekly canakinumab. Responses were lost during the placebo-controlled phase in the placebo group and were regained on resuming canakinumab therapy in the open-label phase. Clinical responses were accompanied by decreases in serum levels of C-reactive protein, serum amyloid A protein, and interleukin-6. HRQoL scores at baseline were considerably below those of the general population. Improvements in all 36-item Short-Form Health Survey (SF-36) domain scores were evident by day 8. Scores approached or exceeded those of the general U.S. population by week 8 and remained stable during canakinumab therapy. Improvements in bodily pain and role-physical were particularly marked, increasing by more than 25 points from baseline to week 8. Therapy was generally well tolerated.ConclusionsCanakinumab, 150 mg, 8-weekly, induced rapid and sustained remission of symptoms in patients with CAPS, accompanied by substantial improvements in HRQoL.Trial registrationClintrials.gov NCT00465985

Hidradenitis Suppurativa and Concomitant Pyoderma Gangrenosum A Case Series and Literature Review

BACKGROUND Hidradenitis suppurativa (HS) and pyoderma gangrenosum (PG) are both rare inflammatory skin conditions that are associated with systemic inflammatory diseases. We performed a retrospective medical chart review of patients with an overlap of HS and PG. OBSERVATIONS We identified 11 cases of PG lesions presenting in patients with HS. Ten of the patients were women, and 9 were obese. All the patients developed HS lesions first, a median of 2.5 years (range, 0-15 years) preceding the appearance of PG lesions. All patients required multiple therapeutic agents because their diseases were often poorly responsive to standard therapies. Two patients received tumor necrosis factor inhibitors; 1 responded to treatment. One patient was treated with anakinra (interleukin-1 receptor antagonist) and had a 75% improvement of her lesions. CONCLUSIONS We have identified a group of patients who have an overlap of PG and HS. Pyoderma gangrenosum can appear at any point after the development of HS and often has a severe, refractory course. We propose that PG and HS may represent variant manifestations of cytokine dysregulation by the innate immune system with common etiology. New therapeutic agents are eagerly sought, and further investigation with regard to interleukin 1 blockade is warranted.

Cryopyrin-Associated Periodic Syndrome: An Update on Diagnosis and Treatment Response

Cryopyrin-associated periodic syndrome (CAPS) is a rare hereditary inflammatory disorder encompassing a continuum of three phenotypes: familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and neonatal-onset multisystem inflammatory disease. Distinguishing features include cutaneous, neurological, ophthalmologic, and rheumatologic manifestations. CAPS results from a gain-of-function mutation of the NLRP3 gene coding for cryopyrin, which forms intracellular protein complexes known as inflammasomes. Defects of the inflammasomes lead to overproduction of interleukin-1, resulting in inflammatory symptoms seen in CAPS. Diagnosis is often delayed and requires a thorough review of clinical symptoms. Remarkable advances in our understanding of the genetics and the molecular pathway that is responsible for the clinical phenotype of CAPS has led to the development of effective treatments. It also has become clear that the NLRP3 inflammasome plays a critical role in innate immune defense and therefore has wider implications for other inflammatory disease states.

Psoriasis patients are enriched for genetic variants that protect against HIV-1 disease

An important paradigm in evolutionary genetics is that of a delicate balance between genetic variants that favorably boost host control of infection but which may unfavorably increase susceptibility to autoimmune disease. Here, we investigated whether patients with psoriasis, a common immune-mediated disease of the skin, are enriched for genetic variants that limit the ability of HIV-1 virus to replicate after infection. We analyzed the HLA class I and class II alleles of 1,727 Caucasian psoriasis cases and 3,581 controls and found that psoriasis patients are significantly more likely than controls to have gene variants that are protective against HIV-1 disease. This includes several HLA class I alleles associated with HIV-1 control; amino acid residues at HLA-B positions 67, 70, and 97 that mediate HIV-1 peptide binding; and the deletion polymorphism rs67384697 associated with high surface expression of HLA-C. We also found that the compound genotype KIR3DS1 plus HLA-B Bw4-80I, which respectively encode a natural killer cell activating receptor and its putative ligand, significantly increased psoriasis susceptibility. This compound genotype has also been associated with delay of progression to AIDS. Together, our results suggest that genetic variants that contribute to anti-viral immunity may predispose to the development of psoriasis.

An open-label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa

BACKGROUND Hidradenitis suppurativa (HS) is a chronic inflammatory disorder characterized by sterile abscesses and fistulae predominantly affecting the axillae and groin. Various biologic agents have been attempted for HS, but there is still no definitive treatment. OBJECTIVES We sought to evaluate the efficacy, safety, and tolerability of anakinra in the treatment of moderate to severe HS. METHODS Six patients with moderate to severe HS were enrolled in an open-label study with all patients receiving active treatment for 8 weeks with an additional 8 weeks of follow-up off therapy. RESULTS The 5 patients who completed the 8-week therapy showed a significant mean decrease in their modified Sartorius score of 34.8 points. The physician and patient global assessment of overall activity showed significant reductions between baseline and 8 weeks of therapy: 45.8 points and 35.6 points, respectively. The Dermatology Life Quality Index showed a significant reduction after 8 weeks of treatment with anakinra. Functional T-cell analysis revealed that patients had increased percentages of CD3(+) T cells in lesional skin compared with nonlesional skin before therapy. LIMITATIONS The limited number of patients and lack of control group are limitations. CONCLUSIONS Anakinra demonstrated decreased HS disease activity by both objective and subjective measures.

Immunosenescence is associated with presence of Kaposi's sarcoma in antiretroviral treated HIV infection.

Objective:Some antiretroviral treated HIV-infected patients develop Kaposis sarcoma despite long-term suppression of HIV replication. These Kaposis sarcoma lesions are consistent with Kaposis sarcoma observed in the elderly uninfected population (’classical Kaposis sarcoma’). We investigated potential mechanisms for this phenomenon, focusing on measures of immune activation and T-cell senescence. Design:We compared markers of immunosenescence, naive T cells, activation, and inflammation in CD4+ and CD8+ T cells from antiretroviral-treated participants with new-onset Kaposis sarcoma (cases, n = 19) and from treated individuals without Kaposis sarcoma (controls, n = 47). Results:There was increased frequency of CD4+ and CD8+ T cells with an immunosenescence phenotype (CD57+ and CD28−) in cases vs. controls (CD4+T cells: CD57+ 7.4 vs. 3.7%, P = 0.025; CD28− 9.1 vs. 4.8%, P = 0.025; CD8+ T cells: CD57+ 41.5 vs. 27.7%, P = 0.003; CD28− 60.5 vs. 51.3%, P = 0.041). Cases had lower proportions of naïve T cells (CD27+CD28+CD45RA+) in CD4+ (23.0 vs. 32.2%, P = 0.023) and CD8+ (11.3 vs. 20.7%, P < 0.001) T-cell compartments. CCR5 was more highly expressed in CD4+ (16.3 vs. 11.0%, P = 0.025), and CD8+ (43.1 vs. 28.3%, P <0.001) T-cell compartments in cases vs. controls. There was no difference in telomere length or telomerase activity in peripheral blood mononuclear cells, or in T-cell expression of activation markers (HLADR+CD38+). Conclusion:Among antiretroviral-treated patients, increased frequencies of T cells with an immunosenescence phenotype and lower frequencies of naive T cells were associated with presence of Kaposis sarcoma among effectively treated patients. These data suggest that certain immunologic perturbations –including those associated with aging – might be causally associated with development of Kaposis sarcoma.