piperidines and Sarcoidosis

Sarcoidosis is a complex granulomatous disease of unknown cause. Corticosteroids and immune suppressants are often given long term in chronic disease, which may result in substantial toxicity. Validated strategies for selecting patients at risk for disease progression, who might benefit from early and targeted treatment, are lacking. Consequently, the unmet need for new treatment options in sarcoidosis is high. In this review, we critically discuss potential therapeutic targets and ongoing clinical trials in sarcoidosis.. Despite the heterogeneous clinical manifestations and the lack of a reliable animal model, our knowledge and understanding of the pathogenesis of sarcoidosis has improved in recent years, which has resulted in the identification of several potential therapeutic strategies. They include the inhibition of cytokines involved in maturation of macrophages, activation of dendritic cells, and maturation and activation of pathogenic T-lymphocytes. The inflammasome and the autophagy are additional areas for future research. Antifibrotic therapy might also be a reasonable choice in selected patients, although the best treatment strategy in progressive fibrotic sarcoidosis remains undetermined.. In this article, we review novel approaches to sarcoidosis treatment and potential therapeutic targets.

Topics: Adrenocorticotropic Hormone; Anti-Inflammatory Agents, Non-Steroidal; Autophagy; Biological Products; Cytokines; Dendritic Cells; Fibrosis; Glucocorticoids; Humans; Immunosuppressive Agents; Inflammasomes; Macrophages; Molecular Targeted Therapy; Piperidines; Protein Kinase Inhibitors; Pyridones; Pyrimidines; Sarcoidosis; T-Lymphocytes

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4

Topics: Cytokines; Humans; Piperidines; Pyrimidines; Sarcoidosis

Topics: Glucocorticoids; Humans; Janus Kinase Inhibitors; Janus Kinases; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Sarcoidosis

Topics: Humans; Menthol; Piperidines; Pyrimidines; Sarcoidosis

Topics: Humans; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Sarcoidosis

Blau syndrome (BS), a rare, autosomal-dominant autoinflammatory syndrome, is characterized by a clinical triad of granulomatous recurrent uveitis, dermatitis, and symmetric arthritis and associated with mutations of the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Aim of this study was to assess the efficacy of tofacitinib in Chinese paediatric patients with BS.. Tofacitinib was regularly administered to three BS patients (Patient 1, Patient 2, and Patient 3) at different dosages: 1.7 mg/day (0.11 mg/kg), 2.5 mg/day (0.12 mg/kg), and 2.5 mg/day (0.33 mg/kg). The clinical manifestations of the patients, magnetic resonance imaging results, serological diagnoses, therapeutic measures and outcomes of treatments are described in this report.. The clinical characteristics and serological diagnoses of all BS patients were greatly improved after the administration of tofacitinib treatment. All patients reached clinical remission of polyarthritis and improvements in the erythrocyte sedimentation rate (ESR) and levels of C-reactive protein (CRP) and inflammatory cytokines.. Tofacitinib, a Janus kinase (JAK) inhibitor, is a promising agent for BS patients who have unsatisfactory responses to corticosteroids, traditional disease-modifying antirheumatic drugs, and biological agents.

Topics: Arthritis; Biomarkers; Blood Sedimentation; C-Reactive Protein; Child; Child, Preschool; Cytokines; Electrocardiography; Follow-Up Studies; Humans; Infant; Janus Kinase Inhibitors; Joints; Magnetic Resonance Imaging; Male; Piperidines; Pyrimidines; Sarcoidosis; Synovitis; Time Factors; Uveitis

Topics: Administration, Oral; Aged; Biopsy; Female; Humans; Janus Kinases; Lung; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Retrospective Studies; Sarcoidosis; Sarcoidosis, Pulmonary; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors; Tomography, X-Ray Computed; Treatment Outcome

Anaplastic lymphoma kinase (ALK) rearranged lung cancers represent 4% to 6% of all pulmonary adenocarcinomas, and echinoderm microtubule associated protein like 4 (EML4)-ALK fusions are the most common subgroup. Herein, we report a case of two successive drug reactions due to ALK inhibitors. A 69-year-old female with stage IVB EML4-ALK fused lung adenocarcinoma developed a generalized morbilliform eruption 10 days after starting alectinib. Skin biopsy findings were consistent with a drug reaction. Her findings resolved after alectinib was discontinued. Another ALK inhibitor, lorlatinib was started and she developed multiple asymptomatic cutaneous and oral nodules 4 months later. Biopsies from these nodules showed sarcoidal granulomas without evidence of metastases or infection. ALK inhibitors are associated with numerous adverse events, including various cutaneous eruptions. However, a sarcoidal drug reaction involving the skin has not been reported. Identification of drug reactions to targeted therapy can avoid long-term sequelae and misinterpretation of the clinical findings as disease progression or infection.

Topics: Adenocarcinoma of Lung; Aged; Aminopyridines; Anaplastic Lymphoma Kinase; Biopsy; Carbazoles; Cell Cycle Proteins; Drug-Related Side Effects and Adverse Reactions; Female; Granuloma; Humans; Lactams; Microtubule-Associated Proteins; Neoplasm Staging; Piperidines; Protein Kinase Inhibitors; Pyrazoles; Sarcoidosis; Serine Endopeptidases; Skin; Withholding Treatment

Topics: Adrenal Cortex Hormones; Humans; Pharmaceutical Preparations; Piperidines; Prospective Studies; Pyrimidines; Sarcoidosis; Sarcoidosis, Pulmonary; Steroids

Sarcoidosis and granuloma annulare (GA) are cutaneous granulomatous disorders that can be difficult to treat. There is evidence of underlying Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway activation in sarcoidosis, suggesting that JAK inhibition might be effective.. To evaluate treatment with tofacitinib, a JAK inhibitor, in patients with recalcitrant sarcoidosis and GA.. A prospective evaluation of tofacitinib in 4 consecutive patients with recalcitrant cutaneous sarcoidosis (n = 3) and generalized GA (n = 1) was conducted. Immunohistochemical analysis of skin biopsy specimens from other patients with sarcoidosis (n = 21) and GA (n = 17) was performed to characterize patterns of JAK-STAT pathway activation.. Tofacitinib resulted in a mean improvement in the baseline Cutaneous Sarcoidosis Activity and Morphology Instrument and Granuloma Annulare Scoring Index scores of 96% (standard deviation, 2%). Histologic resolution of disease was documented in all patients (3 out of 3) who had skin biopsies while receiving therapy. Constitutive STAT1 and STAT3 activation was observed in both sarcoidosis and GA, albeit in different patterns. Signal regulatory protein α may explain the differences in JAK-STAT signaling between sarcoidosis and GA.. The study is limited by the small number of participants.. Tofacitinib resulted in dramatic improvement in 4 patients with cutaneous sarcoidosis and GA. Larger studies are underway to better understand this effect.

Topics: Adult; Aged; Biopsy; Female; Granuloma Annulare; Humans; Janus Kinase Inhibitors; Male; Middle Aged; Piperidines; Prospective Studies; Pyrimidines; Pyrroles; Remission Induction; Sarcoidosis; Severity of Illness Index; Skin; Treatment Outcome

Topics: Aged; Azetidines; Female; Granuloma; Humans; Melanoma; Middle Aged; Piperidines; Protein Kinase Inhibitors; Sarcoidosis; Skin Neoplasms; Vemurafenib

There is evidence that Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling plays a role in the pathogenesis of sarcoidosis. We treated a patient with cutaneous sarcoidosis with the JAK inhibitor tofacitinib; the patient had not previously had a response to medications and had not received systemic glucocorticoids. This treatment resulted in clinical and histologic remission of her skin disease. Sequencing of RNA and immunohistochemical examination of skin-lesion samples obtained from the patient before and during therapy and immunohistochemical testing of lesion samples obtained from other patients with cutaneous sarcoidosis support a role for JAK-STAT signaling in cutaneous sarcoidosis. (Funded by the Ranjini and Ajay Poddar Resource Fund for Dermatologic Diseases Research and others.).

Topics: Female; Humans; Immunohistochemistry; Janus Kinases; Middle Aged; Piperidines; Protein Kinase Inhibitors; Pyrimidines; Pyrroles; Remission Induction; Sarcoidosis; Sarcoidosis, Pulmonary; Sequence Analysis, RNA; Signal Transduction; Skin; Skin Diseases; STAT Transcription Factors

An 81-year-old man with cardiac sarcoidosis was scheduled for an open colectomy and partial resection of liver metastasis. He had undergone implantation of a permanent cardiac pacemaker for complete atrioventricular block 5 years before. Preoperative echocardiography revealed severely reduced left ventricular function, with an ejection fraction of 30%. General anesthesia was induced and maintained with remifentanil 0.2 microg x kg(-1) x min(-1), along with a target-controlled infusion of propofol combined with intermittent administrations of low-dose fentanyl. Perioperative hemodynamic monitoring with a pulmonary artery catheter and transesophageal echocardiography was useful for management of cardiac function and control of infusion volume. The surgery was conducted uneventfully and the patient entered the ICU without endotracheal intubation. Thereafter, the postoperative course was stable without major complications. Cardiac sarcoidosis is characterized by a high incidence of complete atrioventricular block, ventricular arrhythmia, and cardiac dysfunction. We consider that a combination of remifentanil and propofol is useful for careful anesthetic management of patients with cardiac sarcoidosis.

Topics: Aged, 80 and over; Anesthesia, Intravenous; Cardiomyopathies; Colectomy; Hepatectomy; Humans; Male; Piperidines; Propofol; Remifentanil; Sarcoidosis; Ventricular Dysfunction, Left