Tofacitinib therapy for severe pyoderma gangrenosum in a patient with enteropathic arthritis: a case-based review.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that is associated with systemic inflammatory conditions. Currently, there is no universally accepted standard therapy for PG, but immunosuppressive (IS) treatment seems essential. We report a patient here who was successfully treated with tofacitinib despite being PG-refractory to multiple anti-tumor necrosis factor alpha (anti-TNF) therapies and conventional IS. In addition, we performed a comprehensive review of all cases of PG treated with JAK inhibitors. We identified 27 cases treated with JAK inhibitors. Approximately 80% of the patients achieved complete recovery within a median of 12 weeks, even though 17 patients (63%) had received biologics before JAKinib treatment. Notably, this recovery could appear as early as 2 weeks. JAK inhibitors may prove useful in the future, particularly for treating immunosuppressive and steroid-resistant pyoderma gangrenosum, according to recent case reports.

Determinants of Six-Minute Walk Test Performance in Women with Systemic Sclerosis.

OBJECTIVES: The aim of this study was to investigate the determinants of six-minute walk test (6MWT) distance in women with systemic sclerosis. METHODS: In this cross-sectional study, 36 women with systemic sclerosis were assessed using the Medsger Systemic Sclerosis Severity Scale (MSS), modified Rodnan Skin Score (mRSS), Health Assessment Questionnaire (HAQ), University of California Scleroderma Clinical Study Consortium Gastrointestinal Tract Scale, quadriceps strength measurement, Milliken Activities of Daily Living Scale (MAS), and International Physical Activity Questionnaire. The 6MWT was performed to assess the participants' functional capacity and examine factors affecting functional capacity. RESULTS: 6MWT distance was moderately associated with disease severity, with 14 participants walking less than 80% of the predicted distance. 6MWT distance was also significantly correlated with spirometry values and MSS, mRSS, HAQ, and MAS scores (p<0.05). In linear regression analysis, MSS and MAS scores were identified as independent predictors of 6MWD and accounted for 42.5% of variance (R2 = 0.425). CONCLUSION: Disease severity and activities of daily living are independently associated with functional capacity in women with scleroderma, with MSS and MAS scores accounting for 42.5% of variance in 6MWT distance in the linear regression model.

Quantitative analysis of JAK/STAT signaling pathway in patients of inflammatory skin disorders.

BACKGROUND: Inflammatory skin diseases (ISDs), are characterized by dysregulated activation of innate and adaptive immune systems, with inflammatory cytokines playing a crucial role in their pathogenesis. OBJECTIVES: This study aimed to investigate the involvement of Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway in the pathogenesis of ISDs. METHODS: The study analyzed a total of 117 skin biopsies, comprising 31 from pyoderma gangrenosum (PG), 25 from hidradenitis suppurativa (HS), 35 from psoriasis patients, and 26 from control subjects. To assess the expression levels of JAK/STAT pathway components, immunohistochemical staining was performed on both the dermal and epidermal layers of the skin. The Histo score (H score) was utilized as the immunoexpression score to evaluate the staining intensity. RESULTS: The results indicated that all components of the JAK/STAT signaling pathway, except JAK2 and STAT6 in PG, JAK1, STAT4, and STAT6 in HS, and JAK1 in psoriasis, were overexpressed in the dermal skin compared to the control group (p < 0.05). Psoriatic skin had higher expression of STAT6 than both PG and HS and higher expression of JAK2 than PG (p < 0.05). Additionally, HS biopsies had higher expression of JAK2 and STAT6 compared to PG (p < 0.05). JAK1 expression was higher in PG than in HS, psoriasis, and the control group (mean H score was 265.8, 184.8, 191.4, and 113.1, p < 0.05, respectively). CONCLUSIONS: This study provides new insights into the potential contribution of the JAK/STAT pathway to the pathogenesis of ISDs. The findings suggest that targeting this pathway could be a promising therapeutic strategy for treating these disorders.

The Effect of Vedolizumab on Spondyloarthritis Symptoms in a Cohort of Inflammatory Bowel Disease Patients.

OBJECTIVE: Vedolizumab is a novel anti-inflammatory molecule that is currently being used in the treatment of refractory inflammatory bowel disease. The mode of action is inhibiting the binding of activated T lymphocytes to the adhesion molecule 1 of intestinal mucosal cells. Due to its local effect, systemic immunosuppression is not expected, and this may have a negative effect on the extra-intestinal symptoms of inflammatory bowel disease, particularly spondyloarthritis. Currently, there is limited data regarding the effect of vedolizumab on spondyloarthritis symptoms. We aimed to investigate whether vedolizumab has an effect on the occurrence of rheumatological symptoms and the clinical course of patients who have spondyloarthritis. METHODS: Thirty-nine adult inflammatory bowel disease patients who were followed up in the Gastroenterology Clinic and treated with vedolizumab were included in the study. Patients were reviewed in terms of rheumatological manifestations. The occurrence of new musculoskeletal findings during the vedolizumab treatment was recorded. Patients with a former diagnosis of spondyloarthritis were evaluated for the activity of axial and peripheral manifestations during the vedolizumab. RESULTS: There were 39 inflammatory bowel disease patients (29 Crohn's disease, 10 ulcerative colitis, 48.7% (n = 19) male) who had been treated with vedolizumab. The mean age of the patients was 41.4 ± 15.7 years, and the duration of inflammatory bowel disease was 10.4 ± 7.5 years. A total of 17 (44%) patients had accompanying spondyloarthritis findings (mean age 47.08 ± 15.325 years and 58.8% M). Seven patients had axial dominant symptoms and 6 of them were in an active disease state before vedolizumab. During vedolizumab, all but 1 continued to be active. There were 14 patients with arthritis/arthralgias before vedolizumab and only 3 had improvement with therapy. On the other hand, there were 3 patients who had new-onset arthralgias/arthritis with vedolizumab. In total, 6 patients needed to stop vedolizumab because of spondyloarthritis activation (n = 2) and uncontrolled inflammatory bowel disease (n = 4), respectively. CONCLUSION: Treatment with vedolizumab seems no effect on both the occurrence and the course of rheumatological manifestations in inflammatory bowel disease patients. Further studies are required to replicate our results.

Vitamin D attenuates elevated oxidative DNA damage in scleroderma patients with organ involvement: A prospective study.

Scleroderma is a rare autoimmune disease characterized by progressive fibrosis of the skin and internal organs. Oxidative damage to macromolecules has been reported to occur in scleroderma. Among the macromolecular damages, oxidative DNA damage is a sensitive and cumulative marker of oxidative stress and is of particular interest because of its cytotoxic and mutagenic effects. Vitamin D supplementation is an important part of treatment, as vitamin D deficiency is a common problem in scleroderma. Furthermore, the antioxidant role of vitamin D has been demonstrated in recent studies. In light of this information, the present study aimed to comprehensively investigate oxidative DNA damage in scleroderma at baseline and to evaluate the contribution of vitamin D supplementation to the attenuation of DNA damage in a prospectively designed study. In accordance with these objectives, oxidative DNA damage in scleroderma was evaluated by measurement of stable damage products (8-oxo-dG, S-cdA, and R-cdA) in urine by liquid chromatography-tandem mass spectrometry (LC-MS/MS); serum vitamin D levels were determined by high-resolution mass spectrometry (HR-MS); VDR gene expression and four polymorphisms in the VDR gene (rs2228570, rs1544410, rs7975232, and rs731236) were analyzed by RT-PCR and compared with healthy subjects. In the prospective part, the DNA damage and the VDR expression of the patients who received vitamin D were re-evaluated after the replacement. As a result of this study, we demonstrated that all DNA damage products were increased in scleroderma patients compared to healthy controls, whereas vitamin D levels and VDR expression were significantly lower (p < 0.05). After supplementation, statistical significance (p < 0.05) was reached for the decrease in 8-oxo-dG and the increase in VDR expression. Attenuated 8-oxo-dG after replacement in patients with lung, joint, and gastrointestinal system involvement demonstrated the efficacy of vitamin D in scleroderma patients with organ involvement. To the best of our knowledge, this is the first study to examine oxidative DNA damage in scleroderma comprehensively and to evaluate the effects of vitamin D on DNA damage using a prospective design.

A challenging etiology of myopathy: The late-onset Pompe disease.

Pompe disease is a rare metabolic disorder that is characterized by the deficiency of the acid aglucosidase. As a result, glycogen accumulates in several tissues including motor neurons, skeletal, cardiac, and smooth muscles. The course of the disease varies according to the type of mutations, and the clinical phenotype can be affected by the enzyme levels. Late-onset Pompe disease (LOPD) is a challenging issue for clinicians as it has a milder phenotype with later onset of symptoms and slower disease progression. One of the most important differentials in the diagnosis of LOPD is inflammatory myositis as both diseases have some common clinical and laboratory features. Herein, we presented a 30-year-old female patient initially diagnosed as polymyositis and treated with immunosuppressive therapy without a benefit on her symptoms and later diagnosed as LOPD.

Comparison of physiological responses after incremental shuttle walking test and 6-minute walk test in patients with systemic sclerosis.

BACKGROUND: The 6­minute walk test (6MWT) is a commonly used to evaluate exercise capacity in patients with systemic sclerosis (SSc), but there was no study using the incremental shuttle walking test (ISWT) for assessing exercise capacity and comparing the patient's cardiorespiratory responses to these tests. The aim was to investigate the usability and determinants of the ISWT in patients with SSc and compare the physiological responses after the ISWT and 6MWT. METHODS: A total of thirty four female patients with SSc were included. Dyspnea during daily activities and knee extensor muscle strength was assessed, skin fibrosis and disease severity were recorded, and 6MWT and ISWT were carried out for the exercise capacity measurement. Pulmonary function test results were recorded from the individuals' medical records for SSc with interstitial lung disease (SSc-ILD) patients. RESULTS: The ISWT distance was significantly correlated with the 6MWT distance (p < 0.001). The 6MWT was correlated with age, modified Rodnan skin score, Medsger severity score, modified British Medical Research Council Questionnaire (mMRC) score, and knee extensor muscle strength (p < 0.05). The 6MWT was correlated with the forced expiratory volume in the first second (FEV1) (lt) and forced vital capacity (FVC) (lt) in patients with SSc-ILD (p < 0.05). The ISWT distance was correlated with age, modified Rodnan skin score, mMRC score, and knee extensor muscle strength (p < 0.05). Age, mMRC, and knee extensor muscle strength explained 33.8% of the variance in 6MWT distance, while age, mMRC, and knee extensor muscle strength explained 51.7% of the variance in the ISWT distance. CONCLUSION: Because of the higher cardiopulmonary responses, and having a more standardized procedure, the ISWT may be preferable for investigating symptom-limited exercise capacity in patients with SSc. Age, dyspnea, and knee extensor muscle strength were the determinants of exercise capacity in patients with SSc.

Global hypomethylation pattern in systemic sclerosis: An application for absolute quantification of epigenetic DNA modification products by 2D-UPLC-MS/MS.

BACKGROUND: Systemic sclerosis (SSc) is a rare autoimmune disease characterized by progressive fibrosis of the skin and internal organs. Besides genetics risk factors, understanding the epigenetic modifications in SSc has been gaining acceleration in recent years. Epigenetic modifications are reversible and defined as druggable targets. In this context, it is highly important to present a systemic perspective to epigenetic modifications of SSc in terms of both pathogenesis and clinical utility. MATERIAL AND METHODS: DNA samples from the whole blood specimens of the 41 SSc patients and 27 healthy controls (HCs) were obtained. Absolute quantification of 5-mC, 5-hmdC, 5-cadC, 5-fdC, and 5-hmdU as the DNA methylation and demethylation products were performed using 2D-UPLC-MS/MS. Demographic data and clinical scores were recorded in detail. RESULTS: 5-hmdU was significantly higher in SSc patients while 5-hmdC was lower compared to the HCs (p < 0.01, p = 0.012 respectively). 5-cadC and 5-fdC had upward trend in SSc (p = 0.064; p = 0.066). These results support that SSc patients tend to have a global hypomethylation pattern. Clinical analyzes revealed that lung, gastrointestinal, joint, and vascular involvement of SSc is also associated with increased demethylation or decreased methylation profile. CONCLUSION: We performed absolute quantification of epigenetic DNA modification products in SSc for the first time. We demonstrated an upward trend in global hypomethylation in SSc. Furthermore, as a result of detailed clinical analyzes, the relationship between lung, GIS, and vascular involvement with epigenetic changes was shown. We believe that absolute quantification of DNA methylation and demethylation products with novel technologies can provide a deep understanding of disease pathogenesis and has the potential to mark an era for developing new therapeutic strategies.

A preliminary study of possible fibrotic role of meprin metalloproteases in scleroderma patients.

Objectives: This study aims to investigate the possible fibrotic role of meprin metalloproteases and possible fibrotic effects of activator protein-1 (AP-1) in scleroderma patients. Patients and methods: Between April 2018 and April 2019, a total of 85 scleroderma patients (9 males, 76 females; mean age: 54.9 years; range, 22 to 80 years) who met the 2013 American College of Rheumatology/European League Against Rheumatism criteria and 80 healthy control individuals (10 males, 70 females; mean age 42.9 years; range, 19 to 65 years) were included. Patients' data and blood samples were collected. Messenger ribonucleic acid expressions of interleukin (IL)-6, AP-1 subunits, and tumor necrosis factor-alpha (TNF-α) were analyzed by quantitative real-time polymerase chain reaction. Serum meprin alpha and beta protein levels were analyzed using the enzyme-linked immunosorbent assay. Results: Meprin alpha and meprin beta protein levels increased in scleroderma patients. The AP-1 subunits (c-Fos, c-Jun), IL-6, and TNF-α increased in scleroderma patients, compared to controls. Conclusion: Our results provide evidence showing that increased meprins levels may be related to AP-1 levels and increased meprins levels may responsible for increased inflammatory TNF-α and IL-6 levels. All these data suggest meprins as promising therapeutic targets to restore the balance between inflammation and extracellular matrix deposition in scleroderma.

Pyomyositis and muscle abscess due to Salmonella enteritidis in a patient with Behçet's syndrome: a case report.

Salmonella infections usually present with gastrointestinal manifestations including enterocolitis especially in immunocompromised patients. Haematogenous dissemination and abscesses are very rare complications of Salmonella species. This case report documents a patient with Behçet's syndrome (BS) who has pyomyositis due to Salmonella species. A 43-year-old male patient with BS presented to the outpatient rheumatology clinic with bilateral acute-onset lower extremity pain. However, over a short time the pain gradually increased and was accompanied by fever. The magnetic resonance scans demonstrated pyomyositis and muscle abscess in the adductor and obturator muscles. The cultures showed Salmonella enteritidis infection. The patient was successfully treated with antibiotic therapy. This case is important since it is one of the first in the literature to report an adult patient with BS and Salmonella pyomyositis.

Acute myocardial infarction associated with clomiphene citrate in a young woman.

Clomiphene citrate is a drug that stimulates ovulation and is commonly used in cases of female infertility. Generally, it is recognized as a safe agent for ovulation induction, but rarely, it is associated with life-threatening conditions. A 36-year-old woman who had been prescribed clomiphene citrate for infertility was admitted to the emergency department for chest pain lasting for 2 hours. She had no history of smoking, and she did not have any cardiac risk factor for myocardial infarction (MI). An electrocardiogram performed on admission revealed ST-elevation in the precordial leads. She was taken to the catheter laboratory for ST-elevation myocardial infarction, and the coronary angiography revealed total occlusion of the midportion of the left anterior descending artery (LAD) with a heavy thrombus burden. The circumflex and right coronary arteries were normal. After balloon dilatation, a 2.75x15-mm drug eluting stent was implanted in the mid part of the LAD. The patient had an uncomplicated recovery. Before discharge, echocardiography revealed apical akinesis; anterior and lateral hypokinesis; and an ejection fraction of 45% with mild mitral regurgitation. Although clomiphene citrate is a relatively safe drug for ovarian stimulation, it has been associated with serious side effects, such as MI. Physicians should be aware of the potential risks of clomiphene citrate, especially in patients with risk factors for coronary artery disease.