I. Koetter

Efficacy and safety of anakinra therapy in pediatric and adult patients with the autoinflammatory Muckle-Wells syndrome

OBJECTIVE Muckle-Wells syndrome (MWS) is an inherited autoinflammatory disease caused by mutations in the NLRP3 gene that result in excessive interleukin-1 (IL-1) release. It is characterized by severe fevers, rashes, arthralgia, and conjunctivitis, leading to sensorineural deafness and amyloidosis. The recombinant IL-1 receptor antagonist anakinra blocks the biologic activity of IL-1. The aim of this study was to determine the short- and long-term efficacy and safety of anakinra therapy in children and adults with severe MWS. METHODS A single-center observational study was performed. Standardized assessments included clinical features, the Disease Activity Score (DAS) for MWS, classic and novel markers of inflammation, and patient-derived measures of health status. The primary outcome was a score of <10 on the DAS for MWS at 2 weeks and at the last followup visit. Measures of MWS disease activity were investigated using descriptive statistics and paired comparative analysis. RESULTS A total of 12 patients with severe MWS (5 children and 7 adults) received anakinra for a median of 11 months (range 5-14 months). The median followup was 11 months (range 5-14 months). Disease activity was significantly lower in all patients at 2 weeks (P = 0.0005). Organ manifestations of MWS improved, as did all patient-derived measures of health status, markers of inflammation, and hearing loss in 2 of the patients. Levels of the novel neutrophil activation biomarker S100A12 followed clinical disease activity. Treatment was well tolerated, and no serious adverse events were observed. CONCLUSION Anakinra was found to be a safe and effective treatment of severe MWS, leading to a significant improvement in disease activity at 2 weeks as well as long-term. Anakinra therapy should therefore be considered in children and adults with severe MWS disease requiring IL-1 blockade.

Interferon alfa-2a: a new treatment option for long lasting refractory cystoid macular edema in uveitis? A pilot study.

Purpose: To perform a prospective pilot study to evaluate interferon alfa-2a (IFN alfa-2a) for the treatment of refractory cystoid macular edema (CME) in endogenous uveitis. Methods: IFN alfa-2a was administered at an initial dose of 3 or 6 million IU (depending on body weight) per day subcutaneously. Afterwards IFN alfa-2a was tapered slowly over 6 months and finally discontinued. If CME relapsed IFN alfa-2a was reinstituted and tapered slowly again to evaluate the lowest maintenance dose to keep remission. Results: A total of 15 eyes of 8 patients with refractory CME due to intermediate or posterior uveitis were included. Ineffective pretreatment consisted of systemic steroids and acetazolamide (all patients) and at least one additional immunosuppressant (6 patients). Six of 8 patients (11 eyes) responded well to IFN alfa-2a and CME resolved completely during 6 months treatment. One patient was lost to follow-up after IFN alfa-2a was stopped. In 1 patient (1 eye) even 19 months after cessation of IFN alfa-2a no recurrence of CME occurred. In 4 patients (8 eyes) IFN alfa-2a had to be reinstituted because CME relapsed. All 4 patients responded again. During a mean follow-up period of 16.4 months since restart of therapy we succeeded in all 4 patients to taper IFN alfa-2a to maintenance doses between 1.5 million IU every second and every sixth day without a recurrence of CME in any of the 8 eyes. Conclusion: IFN alfa-2a can be a treatment option for patients with otherwise treatment resistant uveitic CME.

NLRP3 E311K mutation in a large family with Muckle-Wells syndrome--description of a heterogeneous phenotype and response to treatment.

IntroductionMuckle-Wells syndrome (MWS) is an inherited autoinflammatory disease characterized by fever, rash, arthralgia, conjunctivitis, sensorineural deafness and potentially life-threatening amyloidosis. The NLRP3/CIAS1 E311K mutation caused a heterogeneous phenotype of MWS in a large family. This study analyzes the clinical spectrum, patterns of inflammatory parameters and reports on response to treatment.MethodsA total of 42 patients and family members were screened for the presence of the NLRP3 mutation. Clinical symptoms were reviewed in all family members. Classical (erythrocyte sedimentation rate (ESR, C-reactive protein (CRP)) and novel MWS inflammatory markers (serum amyloid A (SAA), cytokines, cytokine receptor levels) were determined. Patients were treated with the IL-1 inhibitors Anakinra or Canakinumab.ResultsAll 13 clinically affected patients were heterozygous carriers of the amino acid substitution p.Glu311Lys/E311K encoded by exon 3 of the NLRP3 gene, but none of the healthy family members. Disease manifestations varied widely. Except for one child, all carriers suffered from hearing loss and severe fatigue. TNF-α, IL-6, TNF-RI, and TNF-RII levels as well as SAA were elevated in three, two, one, six and ten patients, respectively. Both clinical and laboratory parameters responded quickly and sustainedly to treatment with Anakinra or Canakinumab.ConclusionThe NLRP3 E311K mutation is associated with a heterogeneous clinical spectrum, which may expand the view on MWS presentation. The leading symptom was hearing loss. Pericarditis, a rare but severe clinical feature of MWS, was diagnosed in three patients. One patient had a severe course, which led to renal failure secondary to amyloidosis. IL-1 inhibition leads to rapid and sustained improvement of symptoms.

Treatment of Muckle-Wells syndrome: analysis of two IL-1-blocking regimens

ObjectivesMuckle-Wells syndrome (MWS) is an autoinflammatory disease characterized by excessive interleukin-1 (IL-1) release, resulting in recurrent fevers, sensorineural hearing loss, and amyloidosis. IL-1 inhibition with anakinra, an IL-1 receptor antagonist, improves clinical symptoms and inflammatory markers. Subclinical disease activity is commonly observed. Canakinumab, a fully human IgG1 anti-IL-1β monoclonal antibody, can abolish excess IL-1β. The study aim was to analyze the efficacy and safety of these two anti-IL-1 therapies.MethodsTwo cohorts of patients with severe MWS and confirmed NLRP3 mutation were treated with anakinra and/or canakinumab. Clinical and laboratory features including ESR, CRP, SAA, and the neutrophil marker S100A12 were determined serially. Disease activity was captured by MWS disease activity scores (MWS-DAS). Remission was defined as MWS-DAS ≤5 plus normal CRP and SAA. Treatment efficacy and safety were analyzed.ResultsThe study included 12 anakinra- and 14 canakinumab-treated patients; the median age was 33.5 years (3.0 years to 72.0 years); 57% were female patients. Both treatment regimens led to a significant reduction of clinical disease activity and inflammatory markers. At last follow-up, 75% of anakinra-treated and 93% of canakinumab-treated patients achieved remission. During follow-up, S100A12 levels mirrored recurrence of disease activity. Both treatment regimens had favorable safety profiles.ConclusionsIL-1 blockade is an effective and safe treatment in MWS patients. MWS-DAS in combination with MWS inflammatory markers provides an excellent monitoring tool set. Canakinumab led to a sustained control of disease activity even after secondary failure of anakinra therapy. S100A12 may be a sensitive marker to detect subclinical disease activity.

Familial inflammatory Sneddon’s syndrome—case report and review of the literature

Sneddon’s syndrome (SNS) which originally was a clinical diagnosis, is now regarded as a common clinical manifestation of different disease entities. It has been divided into idiopathic, autoimmune and thromboembolic subsets or in systemic lupus erythematosus (SLE)-associated, antiphospholipid syndrome (APS)-associated and primary forms. Familial occurrence of Sneddon’s syndrome is rare. We present a familial case of Sneddon’s syndrome with inflammatory disease pattern, early disease onset and association with autoimmune thyroid disease and anticardiolipin antibodies. Although most authors reporting on adult cases of SNS consider it a non-inflammatory, thromboembolic process, the study of cases with early onset brings attention to the possible inflammatory origin of the syndrome.

SAT0191 Disease Progression in SSC-Overlap Syndromes is Significantly Different from Limited and Diffuse Cutaneous SSC

Background Overlap syndromes are a very heterogeneous and remarkable group of patients, who present at least two connective tissue diseases (CTDs) at the same time, usually with a specific autoantibody status. Currently it is still debated, whether SSc patients showing signs of overlaps to other connective tissue diseases should be regarded as a specific disease subset. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited (lcSSc) and diffuse cutaneous SSc (dcSSc). Methods We here present the data of a prospective study, involving well-defined 3323 patients, registered (with yearly follow-up informations) in a database of the German network for systemic sclerosis (DNSS). The following statistical methods were used: Kaplan-Meier analysis, cox regression, logistic regression, McNemar test as well as א2test/Fisher’s exact test. Results Among 3323 registered patients, 10% (325/3240) were diagnosed as SSc-overlap syndrome. Of these, 82.5% (268/325) were female with a mean age of 49, 2 ± 1.2 years. Significantly more of them developed musculoskeletal involvement, compared to lcSSc and dcSSc patients (37.8 %, 47.8%; p<0.0001) and carried significantly more often other antibodies (71.1%; p<0.0001), which were separated into U1RNP- (22.7%), Ro- (16.8%), PmScl- (11.5%) antibodies, followed by 10.8% with rheumatoid factors, 7.5% with La-, 5.8% with dsDNA- and 2.8% with Jo-1- and 2.6% with Ku-antibodies. The Kaplan-Meier analysis of the onset of organ involvement revealed a clear inclined position of overlap patients between patients suffering from lcSSc and dcSSc, especially regarding lung fibrosis and heart involvement. Patients suffering from PAH, oesophagus involvement and kidney involvement, overlap and lcSSc patients showed nearly similar curve progression (log rank<0.0001). Furthermore musculoskeletal involvement was significantly more frequent and more progressive in patients with overlap disease, followed by patients with dcSSc and lcSSc (log rank<0.0001). Conclusions These data support the current concept, that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different course of the disease, different proportional distribution of specific autoantibodies and skin/organ involvement. Disclosure of Interest None Declared

Diagnosis of the antiphospholipid syndrome in anticoagulated patients

The antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.ZusammenfassungDas Antiphospholipid-Syndrom ist definiert als venöses oder arterielles thromboembolisches Ereignis und/oder rezidivierende Aborte in Assoziation mit dem Nachweis von Anticardiolipin-Antikörpern (ACL-AK) und/oder eines Lupusantikoagulans (LA). Zur Diagnose ist jeweils der Nachweis eines Labor- und eines klinischen Kriteriums erforderlich. ACL-AK werden immunologisch mittels ELISA nachgewiesen, während zur Detektion eines LA unterschiedliche koagulometrische Tests eingesetzt werden. Letztere können durch Antikoagulantien wie Vitamin-K-Antagonisten oder Heparin beeinflusst werden und daher beim antikoagulierten Patienten falsch positive Befunde ergeben, sodass die Diagnose eines APS anhand eines LA-Nachweises beim antikoagulierten Patienten nur mit Einschränkungen möglich ist. Verschiedene Modifikationen derzeit verfügbarer Tests wurden vorgenommen, um diese Schwierigkeiten zu umgehen, des Weiteren konnten Untersuchungen an großen Patientenkohorten zeigen, dass die Mehrzahl aller Patienten mit Antiphospholipidantikörper-Syndrom ACL-AK aufweist. Nicht desto trotz bleibt die Diagnose beim antikoagulierten Patienten schwierig.SummaryThe antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.

Diagnose des Antiphospholipid-Syndrom beim antikoagulierten Patient: Was gibt es zu beachten?@@@Diagnosis of the antiphospholipid syndrome in anticoagulated patients

The antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.ZusammenfassungDas Antiphospholipid-Syndrom ist definiert als venöses oder arterielles thromboembolisches Ereignis und/oder rezidivierende Aborte in Assoziation mit dem Nachweis von Anticardiolipin-Antikörpern (ACL-AK) und/oder eines Lupusantikoagulans (LA). Zur Diagnose ist jeweils der Nachweis eines Labor- und eines klinischen Kriteriums erforderlich. ACL-AK werden immunologisch mittels ELISA nachgewiesen, während zur Detektion eines LA unterschiedliche koagulometrische Tests eingesetzt werden. Letztere können durch Antikoagulantien wie Vitamin-K-Antagonisten oder Heparin beeinflusst werden und daher beim antikoagulierten Patienten falsch positive Befunde ergeben, sodass die Diagnose eines APS anhand eines LA-Nachweises beim antikoagulierten Patienten nur mit Einschränkungen möglich ist. Verschiedene Modifikationen derzeit verfügbarer Tests wurden vorgenommen, um diese Schwierigkeiten zu umgehen, des Weiteren konnten Untersuchungen an großen Patientenkohorten zeigen, dass die Mehrzahl aller Patienten mit Antiphospholipidantikörper-Syndrom ACL-AK aufweist. Nicht desto trotz bleibt die Diagnose beim antikoagulierten Patienten schwierig.SummaryThe antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.

Diagnose des Antiphospholipid-Syndrom beim antikoagulierten Patient: Was gibt es zu beachten?

The antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.ZusammenfassungDas Antiphospholipid-Syndrom ist definiert als venöses oder arterielles thromboembolisches Ereignis und/oder rezidivierende Aborte in Assoziation mit dem Nachweis von Anticardiolipin-Antikörpern (ACL-AK) und/oder eines Lupusantikoagulans (LA). Zur Diagnose ist jeweils der Nachweis eines Labor- und eines klinischen Kriteriums erforderlich. ACL-AK werden immunologisch mittels ELISA nachgewiesen, während zur Detektion eines LA unterschiedliche koagulometrische Tests eingesetzt werden. Letztere können durch Antikoagulantien wie Vitamin-K-Antagonisten oder Heparin beeinflusst werden und daher beim antikoagulierten Patienten falsch positive Befunde ergeben, sodass die Diagnose eines APS anhand eines LA-Nachweises beim antikoagulierten Patienten nur mit Einschränkungen möglich ist. Verschiedene Modifikationen derzeit verfügbarer Tests wurden vorgenommen, um diese Schwierigkeiten zu umgehen, des Weiteren konnten Untersuchungen an großen Patientenkohorten zeigen, dass die Mehrzahl aller Patienten mit Antiphospholipidantikörper-Syndrom ACL-AK aufweist. Nicht desto trotz bleibt die Diagnose beim antikoagulierten Patienten schwierig.SummaryThe antiphospholipid syndrome is characterized by thromboembolic events and/or recurrent miscarriages in the presence of anticardiolipin antibodies and/or a lupus anticoagulant. Anticardiolipin antibodies are detected by ELISA whereas lupus anticoagulant detection includes a variety of coagulometric tests. However, a large number of patients with suspected antiphospholipid syndrome are anticoagulated with either heparin or coumadin when evaluated for the presence of a lupus anticoagulant and false positive test results may ensue, thus making coagulometric testing unreliable in this situation. Modifications of standard coagulometric tests have been suggested in order to circumvent this problem and studies of several patient cohorts have shown that the majority of patients with the antiphospholipid syndrome are anticardiolipin positive. However diagnosis in patients receiving anticoagulation remains a difficult task.