The effects of Pilates training on respiratory muscle strength in patients with ankylosing spondylitis.

BACKGROUND: Reduction in flexibility and mobility are important factors that lead to impairments in quality of life, reduction of exercise tolerance, and a decreased pulmonary capacity with the progression of Ankylosing Spondylitis (AS). AIM: The purpose of this study was to investigate the effects of Pilates exercises on mobility, quality of life, and respiratory muscle strength in patients with AS. METHODS: Forty patients with AS were randomly divided into two groups as Pilates group and the control group. The Pilates group performed Pilates exercises in supervised group sessions and the control group performed conventional exercises at home three days a week for eight weeks. The main outcome measure was respiratory muscle strength. Secondary outcome measures were forced vital capacity (FVC), forced expiratory volume in one second (FEV1) FEV1/FVC ratio, chest expansion, Bath indices (BASDAI, BASMI), Ankylosing Spondylitis Quality of Life Questionnaire (ASQoL) and six-minute walk test (6MWT). All participants were assessed by a blind assessor at baseline and the end of eight weeks. RESULTS: Thirty-six AS patients (n = 19 in the Pilates group, n = 17 in the control group) completed the study. Respiratory muscle strength, FEV1/FVC, chest expansion, BASDAI, BASMI, ASQoL, and 6MWT significantly improved at the 8th week (p < .05) in the Pilates group, while inspiratory muscle strength, FEV1/FVC, chest expansion, and 6MWT showed significant improvements in the control group at 8th week compared to baseline (p < .05). No significant between-group differences were observed when the change over time values were compared (Δ). CONCLUSION: Both Pilates and home exercises seem to be effective for improving respiratory parameters and functional status in patients with AS. Pilates exercises without using any equipment and additional exercises is found to be useful for improving respiratory functions and disease-related symptoms.

Treatment with biologic DMARDs may not adversely affect lung nodules in rheumatoid arthritis patients.

OBJECTIVE: Lung nodules (LNs) impose diagnostic and therapeutic challenges in patients with rheuma- toid arthritis (RA) due to unpredictable outcomes. Potential induction of nodulosis with the use of con- ventional synthetic DMARDs (csDMARD) and lack of knowledge regarding the effect of biologic disease-modifying anti-rheumatic drugs (bDMARDs)/tofacitinib on the LN raise concerns and have an impact on treatment decisions. This study aims to evaluate the possible effects of the bDMARDs/tofa- citinib and csDMARDS on LNs observed in RA patients. METHODS: Electronic health records of RA patients who had LNs detected on computed tomography (CT) between January 2015 and December 2020 were evaluated retrospectively. Patients with follow- up CT images were included in the study. Baseline and follow-up images were meticulously examined for the number, size, attenuation, and cavity formation. Clinical, histopathologic, and laboratory find- ings were analyzed. RESULTS: Forty-two RA patients with LNs were studied, 21 were on bDMARDs/tofacitinib (11 females, mean age: 59.7 6 8.4) and 21 were on csDMARDs (12 females, mean age: 71.4 6 8.3). The proportion of patients with progressed nodules during follow-up was comparable between groups (six patients in bDMARDs/tofacitinib vs seven patients in csDMARDs). Progression of LNs was observed in six patients in the bDMARDs/tofacitinib group: three in anti-TNFa, two in rituximab, and one in abatacept users and none in tofacitinib users. CONCLUSION: Our results suggest that the risk of progression in LNs in RA patients with use of bDMARDs/tofacitinib might not impose a higher risk compared to csDMARDs. Moreover, bDMARDs/ tofacitinib might result in regression in LNs.

Compliance of Familial Mediterranean Fever Patients With Regular Follow-up Visits and Associated Factors.

BACKGROUND: Follow-up is crucial to detect asymptomatic complications of familial Mediterranean fever (FMF). The current European League Against Rheumatism recommendations state that patients with FMF should be evaluated at least every 6 months to monitor attacks, acute phase response, and proteinuria. OBJECTIVES: This study aimed to assess compliance of FMF patients with regular follow-up visits and the associated factors. METHODS: Adult patients with a diagnosis of FMF who had their initial visit at least over 1 year ago were included. Demographic and socioeconomic data, family history, and comorbid diseases were obtained from medical records. The International Severity Score for FMF and the Autoinflammatory Disease Damage Index scores were calculated. We defined patients as "compliant with follow-up visits" both if they had at least 2 visits during the previous year and a compatible physician's assessment. The characteristics of the compliant and noncompliant patients were compared, and multivariable logistic regression analysis was used to determine the factors influencing visit compliance. RESULTS: Four hundred seventy-four patients with FMF were included. Two hundred thirty (48.5%) were compliant, and 244 (51.5%) were noncompliant with follow-up visits. A family history of FMF in parents, the absence of a family history of FMF in siblings, treatment with biologic agents, concomitant medication use, multisite involvement during FMF attacks, and treatment satisfaction were independent predictors of visit compliance. CONCLUSIONS: Only half of the patients with FMF were compliant with follow-up visits. Better strategies should be implemented to increase the compliance of FMF patients. Identifying independent predictors would help to build one.

Test-retest reliability and validity of the 6 minute stepper test to evaluate functional exercise capacity in patients with ankylosing spondylitis.

OBJECTIVES: The 6-minute stepper test (6MST) is a submaximal test that requires little space to assess exercise capacity compared to the 6-minute walk test (6MWT). The study aims to investigate the test-retest reliability and convergent validity of 6MST and to compare physiological responses, dyspnea, fatigue perception with 6MST and 6MWT in patients with ankylosing spondylitis (AS). METHODS: To test the convergent validity of 6MST, 65 patients performed both 6MWT and 6MST on the first day and correlation between two tests were assessed with Pearson correlation test. In order to investigate the test-retest reliability of the 6MST, 32 of the 65 patients performed 6MST one week later and intraclass correlation coefficients (ICC) were calculated. Dyspnea and fatigue perception were analyzed with using Wilcoxon signed-rank test, physiological responses were analyzed using paired sample t-test. RESULTS: Excellent test-retest reliability was observed for 6MST (ICC: 0.988). There was a significant correlation between 6MST and 6MWT (r: 0.725, p < 0.001). Dyspnea and leg fatigue perception were significantly higher in 6MST (p < 0.05). Physiological responses and fatigue perception were similar in both 6MST and 6MWT (p > 0.05). CONCLUSION: This study demonstrated that the 6MST is reliable and valid method to evaluate exercise capacity in patients with AS. 6MST can be used to evaluate exercise capacity of patients with AS.

Diagnostic utility of serum biomarkers in large vessel vasculitis and their correlation with positron emission tomography.

OBJECTIVES: To investigate the association between vascular inflammation, as detected by positron emission tomography (PET) imaging and interleukin-6 (IL-6), pentraxin3, and B-cell-activating factor (BAFF) in subjects with LVV. METHODS: The study included newly diagnosed giant cell arteritis (GCA, n = 27) or Takayasu arteritis (n = 9) patients and healthy control (HC, n = 31) subjects. PET scan and blood samples were obtained before the introduction of treatments. IL-6, PTX3, and BAFF levels were determined quantitatively by enzyme-linked immunosorbent assay kits. RESULTS: Thirty-six patients with LVV (20 females, 16 males; age 64.5 ± 16.6 years) and 31 HC (14 females, 17 males; age 37.1 ± 9.6 years) were included. Serum levels of IL-6, PTX3, and BAFF were increased in patients with newly diagnosed LVV compared with healthy control subjects. In receiver operating characteristics (ROC) analysis, serum IL-6 and BAFF provided excellent discrimination of newly diagnosed LVV patients from HC (area under the ROC curve of >0.90 and >0.80, respectively). None of the inflammatory markers correlated with vascular inflammatory activity determined by PET scanning. CONCLUSIONS: Our results suggest that IL-6 and BAFF may serve as markers of large vessel vasculitis, while PTX3 is not useful. None of the inflammatory markers correlated with PET assessed vasculitis activity.

[Investigation of the Relationship of Systemic Immune-Inflammation Index, C-Reactive Protein and Interleukin-6 with Viral Dynamics in Patients with COVID-19]. / COVID-19 Tanili Hastalarda Sistemik Immün-Enflamasyon Indeksi, C-Reaktif Protein ve Interlökin-6'nin Viral Dinamik ile Iliskisinin Arastirilmasi.

Coronaviruses are enveloped, positivepolarity, single-stranded RNA viruses that can cause respiratory and gastrointestinal tract infections, less likely to cause infections with hepatic, neurological and nephrotic involvement. A novel coronavirus termed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged in the city of Wuhan, China, and caused an outbreak of unusual viral pneumonia at the end of 2019. This study aimed to reveal the relationship between systemic immune-inflammation index (SII), C-reactive protein (CRP) and interleukin-6 (IL-6) and viral dynamics in COVID-19 patients. This retrospective, single-center study was conducted in Ankara City Hospital from April 1 to May 31, 2020. A total of 338 hospitalized patients who had positive results in SARS-CoV-2 reverse transcrytase polymerase chain reaction (RT-PCR) test from nasopharyngeal and oropharyngeal samples during their hospital admission were included in this study. Patients were divided into three groups according to their ward/intensive care unit, intubation and mortality situation and their clinical data were evaluated. Correlation analysis was performed to determine the relationship between viral dynamics and laboratory parameters such as SII, the neutrophil-to-lymphocyte ratio (NLR), the lymphocyte-to-CRP ratio (LCR), the lymphocyte-to-monocyte ratio (LMR), the platelet-to-lymphocyte ratio (PLR), CRP, IL-6 ferritin, albumin levels and lymphocyte count. Advanced age, low Ct value, increase in IL-6, increase in SII, decrease in albumin, increase in ferritin, decrease in lymphocyte count, increase in NLR, decrease in LCR, decrease in LMR, increase in PLR and increase in CRP levels were found statistically significantly different in all three groups (p<0.001; p= 0.02; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001; p<0.001, respectively). Statistical analysis revealed a significant negative correlation between serum IL-6, NLR, LCR and CRP values with Ct values (p<0.01, r= -0.233; p= 0.021, r= -0.126; p=0.004, r= -0.156 and p= 0.011, r= -0.138, respectively) and a significant positive correlation between Ct values and lymphocyte count and albumin levels (p= 0.005; r= 0.151 and p= 0.050; r= 0.106, respectively). Severe progression was observed in patients with advanced age, low Ct value, high IL-6 levels, high SII, hypoalbuminemia, high ferritin levels, lymphopenia, high NLR, low LCR, low LMR, high PLR and high CRP. In these patients hospitalization in intensive care unit, intubation and mortality were found to be higher. High levels of IL-6, NLR, LCR and CRP, lymphopenia and hypoalbuminemia were associated with low PCR Ct values.

Phenotypic characterization of Familial Mediterranean Fever patients harboring variants of uncertain significance

Background/aim: Familial Mediterranean Fever (FMF) is the prototype of hereditary autoinflammatory disorders and caused by mutations on the MEFV gene located on the short arm of chromosome 16. Although some MEFV variants are clearly associated with disease phenotype, there are numerous variants with unknown clinical association which are termed as variants of uncertain significance (VUS). Here, we present clinical correlations of VUS in a large cohort of adult FMF patients from three tertiary centers located in Central Anatolia. Materials and methods: All patients were recruited from FMF in Central Anatolia (FiCA) cohort. Demographic (sex, age at disease onset) and clinical features (disease characteristics, attack frequency, mean colchicine dose, colchicine nonresponsiveness, amyloidosis, and persistent inflammation) of patients with VUS were compared with those harboring pathogenic variants. Disease severity and damage were also evaluated using international severity score for FMF (ISSF) and autoinflammatory disease damage index (ADDI), respectively. Results: Among 971 participants included, MEFV gene analysis results were available for 814 patients. Twenty-six (3.2%) patients had single heterozygous VUS and 54 (6.6%) had pathogenic/VUS complex heterozygous variants. Patients with single heterozygous VUS had similar demographic/clinical features, ISSF and ADDI scores compared to those with single heterozygous pathogenic variant (p > 0.05 for all). No difference was observed in the demographic and clinical features of patients with single heterozygous pathogenic mutation and pathogenic/VUS complex heterozygous variant (p > 0.05 for all). ISSF and ADDI scores were lower in pathogenic/VUS complex heterozygous patients than those harboring single pathogenic mutation (p = 0.006 and 0.004, respectively). Conclusion: Our findings suggest that patients with single heterozygous VUS has mild FMF phenotype similar to those with single pathogenic mutation. Pathogenic/VUS complex heterozygosity does not lead to a more severe clinical phenotype than having a single pathogenic variant.

Appendectomy history is associated with severe disease and colchicine resistance in adult familial Mediterranean fever patients

Background/aim: Peritonitis attacks of Familial Mediterranean Fever (FMF) usually requires emergency medical admissions and it's hard to distinguish a typical abdominal attack from surgical causes of acute abdomen. Therefore, history of abdominal surgery, particularly appendectomy, is very common in patients with FMF. However, history of appendectomy might also give some clues about the course of FMF in the adulthood. This study was to determine whether the history of appendectomy help to anticipate disease course of FMF in the adulthood. Materials and methods: All patients recruited from FMF in Central Anatolia (FiCA) cohort, comprising 971 adult subjects. All patients fulfilled the Tel Hashomer criteria. Demographic data, FMF disease characteristics, co-morbid conditions, past medical history, surgical history and disease complications were meticulously questioned and laboratory features and genotype data (if available) were recruited from patient files. Results: Appendectomy history was evident in 240 (24.7%) subjects. Disease onset was earlier and peritonitis is strikingly more prevalent (97.1% vs. 89.6%, p < 0.001) in appendectomized patients. These patients had reported almost two fold more frequent attacks in the last year compared to appendix intact patients (median 3.5 vs. 2 attacks, p = 0.001) without a difference in frequency of musculoskeletal and skin attacks. Severe disease was more common (10% vs. 5.9%, p = 0.038) due to involvement of more attack sites throughout the life and more frequent attacks. Appendectomy patients had used higher daily doses of colchicine to control disease (1.43 ± 0.6 mg vs. 1.27 ± 0.52 mg, p = 0.002) but colchicine resistance was also more common in these patients, 15% vs. 6.7% respectively, p < 0.001. Conclusion: Appendectomy history is common in FMF patients and associated with frequent serositis attacks in adulthood. These patients require higher colchicine doses with a lower rate of response and more need for Interleukin-1 antagonist therapies.

Predictors of persistent inflammation in familial Mediterranean fever and association with damage.

OBJECTIVE: Persistent inflammation is an insidious and less studied feature of FMF. We investigated clinical determinants of persistent inflammation and its associations with individual damage items. METHODS: This is a cross-sectional analysis of 917 FMF patients, who fulfilled the Tel Hashomer criteria and had at least 6 months' follow-up. Patients were stratified based on whether they had persistent inflammation. We used logistic regression analysis to investigate independent predictors of persistent inflammation and the associated individual damage items. RESULTS: One hundred and forty-two (15%) patients had persistent inflammation. Active FMF (54%) was the most prominent reason for the persistent inflammation. Spondylarthritis (16%), other inflammatory arthritis (8%) and IBD (2%) were other frequent reasons. Male gender, history of exertional leg pain, inflammatory comorbidities, M694V homozygosity, colchicine resistance, lower education levels and musculoskeletal attack dominance were found to be the independent predictors of persistent inflammation. Earlier disease onset led to a tendency towards persistent inflammation. Patients with persistent inflammation were more likely to suffer damage. There is an increased risk of developing proteinuria, amyloidosis and renal insufficiency. CONCLUSION: We identified, for the first time, the predictors of persistent inflammation in adult FMF patients and related individual damage items of the Autoinflammatory Disease Damage Index. Persistent inflammation is insidious and one of the chief causes of damage; therefore, especially patients with these predictors should be followed up more closely. If detected, underlying inflammatory comorbidities should be assessed meticulously as early detection and proper treatment strategies may favourably impact the natural history of the disease.

Diagnostic Role of 18F-Fluorodeoxyglucose Positron Emission Tomography for the Evaluation of Patients With Inflammation of Unknown Origin.

BACKGROUND: Sometimes, the underlying causes of inflammation cannot be established despite meticulous investigation, including medical history, physical examination, laboratory tests, and radiologic procedures. Rheumatologists are often faced with patients whose condition is known as inflammation of unknown origin (IUO). Differential diagnosis of IUO is diverse, and investigation of these cases is challenging and time-consuming. OBJECTIVE: The study aimed to assess the diagnostic role of positron emission tomography/computed tomography (PET/CT) in the evaluation of patients with IUO. METHODS: The study sample consisted of 97 adult patients with IUO who have not been previously diagnosed with an infectious, inflammatory, or malignant disease. The necessary data were collected from January 2015 to June 2018 with a 6-month follow-up period. The patients were screened using PET/CT after a specific diagnosis could not be established with detailed laboratory and radiologic evaluations. RESULTS: A final diagnosis was established at follow-up, and 47 (54%) of the 97 patients had inflammatory diseases, 30 (34.4%) had malignancies, and 10 (11.4%) had infections. Despite meticulous investigation, 10 patients were left undiagnosed in the follow-up. PET/CT aided diagnosis in 59 patients (60.8%), but it was not helpful in 38 patients (39.2%). PET/CT was positive in 30 (63%) of the 47 patients with inflammatory diseases, whose final diagnosis was inflammatory rheumatic disease, as follows: large-vessel vasculitis in 19 patients, polymyalgia rheumatica in 7 patients, and seronegative arthritis or other rare miscellaneous diseases in 4 patients. The sensitivity of PET/CT was 67% with a specificity and diagnostic accuracy of 100% and 71%, respectively. CONCLUSIONS: Investigation of the underlying etiology of IUO is time-consuming and challenging. PET/CT may help identify the final diagnosis more quickly by locating an obscure inflammatory site; thus, it may reduce the number of unnecessary biopsies, diagnostic time, anxiety, work loss, morbidity, and mortality.

Use of prognostic nutritional index in the evaluation of disease activity in patients with Behçet's disease.

OBJECTIVE: Behçet's disease (BD) is a chronic, multisystem disorder that can cause severe morbidity and mortality. Monitoring tools that measure disease activity are required for effective management of BD. We aimed to investigate the association of prognostic nutritional index (PNI) with disease activity in BD. METHODS: In this cross-sectional study, we enrolled 88 adult patients with BD and 51 healthy controls. The patients were divided into patients with active and inactive BD according to their disease activities. PNI was calculated using the following formula: 10×serum albumin (g/dL)+0.005×peripheral lymphocyte count (per mm3). To evaluate BD activity, the Behçet Disease Current Activity Form was used. The relations of BD activity with PNI, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, erythrocyte sedimentation rate, and C-reactive protein were investigated. A receiver operator characteristic curve analysis was used to define the optimum cutoff value of PNI for active BD. RESULTS: A total of 48 patients were classified as having active BD and 40 as having inactive BD. Patients with active BD had lower mean PNI than patients with inactive BD and healthy controls (51.8±4.2, 57.4±2.9, and 56.6±3.6, respectively; p<0.001). In multivariate analysis, PNI was the only independent predictor of BD activity (odds ratio, -0.687; 95% confidence interval 0.548-0.861; p=0.001). The optimum cutoff of PNI for active BD was 55.35 with 79.2% sensitivity and 77.75% specificity. CONCLUSION: PNI was significantly associated with BD activity. PNI may be a useful tool for the assessment of disease activity in BD.

Colchicine intolerance in FMF patients and primary obstacles for optimal dosing

Background/aim: Colchicine is the mainstay of treatment in FMF. However, in daily practice it is not easy to maintain effective colchicine doses in a substantial number of patients due to its side effects. In this study, we aimed to investigate prevalence and risk factors for colchicine side effects that limit optimal drug dosing and cause permanent discontinuation. Materials and methods: All patients were recruited from "FMF in Central Anatolia" (FiCA) cohort, 915 adults with a minimum follow- up time of 6 months during which they had obeyed all treatment instructions. Demographic and anthropometric data, FMF disease characteristics, disease severity, complications, and treatment features were recorded on a web-based registry. Prevalence of colchicine intolerance and characteristics of intolerant patients were analyzed. Results: Effective colchicine doses cannot be maintained in 172 (18.7%) subjects. Main side effects that limit optimal dosing were as follows: diarrhea in 99 (10.8%), elevation in transaminases in 54 (5.9%), leukopenia in 10 (%1.1), renal impairment in 14 (1.3%), myopathy in five (0.5%), and allergic skin reaction in two. Colchicine had to be permanently ceased in 18 (2%) patients because of serious toxicity. Male sex and obesity were found to be associated with liver toxicity, and having a normal body weight was associated with diarrhea. Chronic inflammation and proteinuria were more common in colchicine-intolerant patients, and they had reported more frequent attacks compared to those tolerating optimal doses. Conclusion: Colchicine intolerance is an important problem in daily clinical practice, mainly due to diarrhea and liver toxicity. Suboptimal colchicine dosing is associated with complications.

Factors associated with damage in patients with familial Mediterranean fever.

OBJECTIVES: Defining predictors of damage would improve patient care. We applied damage indexes to patients with familial Mediterranean fever (FMF) and identified the predictors of damage. METHODS: This is a cross-sectional analysis of 926 FMF patients, who fulfilled the Tel-Hashomer criteria and had at least six months of follow-up. Patients were stratified according to their damage status (damage vs. no damage) defined with autoinflammatory disease damage index (ADDI) and modified ADDI (excluding musculoskeletal pain). We used logistic regression analysis to investigate independent predictors of damage for both indexes. RESULTS: Mean disease duration was 21.6±11.9 years. 527 patients (57%) had damage according to ADDI. Median ADDI score was 1 (0-11). Most common FMF-related damages were observed in musculoskeletal, reproductive and kidney domains. Female gender, inflammatory comorbidity, colchicine resistance, colchicine nonadherence, musculoskeletal attack dominance, diagnostic delay, follow-up time, and smoking history remained independent predictors of damage according to ADDI score. The rate of patients with damage defined by modified ADDI was only to 23%. M694V/M694V homozygosity, female gender, musculoskeletal attack dominance, colchicine resistance, persistent inflammation, follow up time and family history of amyloidosis were found to be predictors of damage according to modified ADDI score. CONCLUSIONS: Our study is the first to apply comprehensive damage indexes to FMF patients and identified predictors of damage. Factors linked to a severe FMF phenotype, including M694V homozygosity and persistent inflammation, were associated with only modified ADDI. Our findings justify the concerns about musculoskeletal pain and might point to the need for re-evaluation of ADDI for FMF patients.

Importance of 14-3-3eta, anti-CarP, and anti-Sa in the diagnosis of seronegative rheumatoid arthritis

Background/aim: Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation. The study aimed to assess serum 14-3-3eta, anti-CarP, and anti-Sa in seronegative RA (SNRA) patients who were treatment-naïve as well as in healthy subjects. This is the first study in the literature to examine these autoantibodies together in SNRA patients. Materials and methods: Forty-five treatment-naïve SNRA patients and 45 healthy subjects were recruited. Drugs change the levels of autoantibodies; therefore, patients who took any medication had been excluded from our study. Anti-carbamylated protein, anti-Sa, and 14-3-3eta were measured by using three different ELISA kits. Results: Median serum concentration of healthy controls in 14-3-3eta was 0.02 (0.02­0.27) ng/mL. Median serum concentration of SNRA patients in 14-3-3eta was 1.00 (0.48­1.28) ng/mL. Data were analyzed with Mann­Whitney U tests; the P-value was <0.001 in 14-3-3eta. Receiver operating characteristic (ROC) curve analysis showed that 14-3-3eta in SNR compared to healthy controls had a significant (P < 0.001) area under the curve (AUC) of 0.90 (95% confidence interval, 0.83­0.96). At a cutoff of ≥0.33 ng/mL, the ROC curve yielded a sensitivity of 88.9%, a specificity of 82.2%, a positive predictive value of 83.3%, and a negative predictive value of 88.1%. Conclusion: We found that 14-3-3eta can be used as a diagnostic marker in SNRA.

Certolizumab Pegol Treatment in Three Patients With Takayasu Arteritis.

Although glucocorticoids are the mainstay of treatment in Takayasu arteritis (TA), anti-tumor necrosis factor agents are other treatment options in refractory disease. The onset of TA is generally observed in females of reproductive age. Certolizumab pegol (CZP) lacks a fragment crystallizable region and this gives advantage of minimal transfer through the placenta, which makes CZP a safer option in pregnancy. Although there are case reports and trials about use of infliximab, etanercept, and adalimumab in TA, there are scarce data about use of CZP. In this article, we present three TA cases treated with CZP. While two patients benefited from CZP, one patient was refractory to CZP.