Rheumatic immune-related adverse events induced by immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICIs) block the major inhibitory pathways in T cells, resulting in an augmented antitumor response. Immune-related adverse events (irAEs) are a new class of side effects caused by ICIs and tend to be more prevalent in patients with preexisting autoantibodies and autoimmune diseases. The rheumatic subset of irAEs mainly includes arthralgia, arthritis, myalgia, myositis, vasculitis, sicca syndrome, scleroderma and systemic lupus erythematosus. The most common classification system for AEs, the Common Terminology Criteria for Adverse Events, is of limited use for irAEs, especially rheumatic irAEs. Therapy with glucocorticoid and temporary or permanent discontinuation of ICIs are the cornerstones of irAE treatment, and can be complemented with immunosuppressants (e.g., methotrexate), biologic agents (e.g., tumor necrosis factor inhibitors and interleukin-6 receptor antagonists), intravenous immunoglobin and plasma exchange. Thus, the evaluation and treatment of rheumatic irAEs require multidisciplinary cooperation among physicians. Here, we review the most prevalent ICI-associated rheumatic irAEs.

Mitigation of Rheumatic Arthritis in a Rat Model via Transdermal Delivery of Dapoxetine HCl Amalgamated as a Nanoplatform: In vitro and in vivo Assessment.

PURPOSE: Dapoxetine HCl (DH), a selective serotonin reuptake inhibitor, may be useful for the treatment of rheumatic arthritis (RA). The purpose of this study was to investigate the therapeutic efficacy of transdermal delivery of DH in transethosome nanovesicles (TENVs). This novel delivery of DH may overcome the drawbacks associated with orally administered DH and improve patient compliance. METHODS: DH-TENV formulations were prepared using an injection- sonication method and optimized using a 33 Box-Behnken-design with Design Expert® software. The TENV formulations were assessed for entrapment efficiency (EE-%), vesicle size, zeta potential, in vitro DH release, and skin permeation. The tolerability of the optimized DH-TENV gel was investigated using a rat skin irritation test. A pharmacokinetic analysis of the optimized DH-TENV gel was also conducted in rats. Moreover, the anti-RA activity of the optimized DH-TENV gel was assessed based on the RA-specific marker anti-cyclic cirtullinated peptide antibody (anti-CCP), the cartilage destruction marker cartilage oligomeric matrix protein (COMP) and the inflammatory marker interleukin-6 (IL-6). Level of tissue receptor activator of nuclear factor kappa-Β ligand (RANKL) were also assessed. RESULTS: The optimized DH-TENV formulation involved spherical nanovesicles that had an appropriate EE- % and skin permeation characteristic. The DH-TENV gel was well tolerated by rats. The pharmacokinetics analysis showed that the optimized DH-TENV gel boosted the bioavailability of the DH by 2.42- and 4.16-fold compared to the oral DH solution and the control DH gel, respectively. Moreover, it significantly reduced the serum anti-CCP, COMP and IL-6 levels and decreased the RANKL levels. Furthermore, the DH-TENV gel attenuated histopathological changes by almost normalizing the articular surface and synovial fluid. CONCLUSION: The results indicate that DH-TENVs can improve transdermal delivery of DH and thereby alleviate RA.

Vascular Arginase Is a Relevant Target to Improve Cerebrovascular Endothelial Dysfunction in Rheumatoid Arthritis: Evidence from the Model of Adjuvant-Induced Arthritis.

Emerging data revealed that rheumatoid arthritis (RA) is associated with higher risk of cerebrovascular diseases. Whereas cerebral endothelial dysfunction is acknowledged as a critical aspect of cerebrovascular diseases, its presence in RA and the mechanisms involved are currently unknown. By using the model of rat adjuvant-induced arthritis (AIA), the present study investigated cerebrovascular reactivity in pressurized middle cerebral arteries (MCA) on day 33 post-immunization. The results revealed that arthritis induced a dramatic decrease in the vasodilatory response to acetylcholine (ACh), ADP, and bradykinin (n = 7-9 arteries, p < 0.0001). By using nor-NOHA, L-NAME, BH4, and Tempol, the results showed that the reduced response to ACh relied on arginase overactivation (n = 8), low NOS activity (n = 8), BH4 deficiency (n = 9), and excessive superoxide production (n = 9). Immunohistological analysis revealed an endothelial upregulation of arginase 2 (p < 0.05, n = 5-6) and NADPH oxidase (p < 0.05, n = 5-7) while eNOS expression was unchanged in AIA (n = 6). To assess whether arginase inhibition may be a relevant therapeutic, AIA rats were treated with an arginase inhibitor (nor-NOHA, 40 mg/kg/day, i.p., n = 20 rats) daily from day 10 to day 33 post-immunization. The treatment alleviated the impaired response of MCA to endothelium-dependent agonists, through an increase in NOS signaling and a suppression of BH4 deficiency and superoxide overproduction. By contrast, it did not change the course of arthritis. In conclusion, arthritis induced a cerebrovascular endothelial dysfunction involving an imbalance in the arginase/NOS pathway. Arginase inhibition appears as a promising therapy beyond anti-rheumatic drugs for reducing the risk of cerebrovascular diseases in RA.

Report: Metformin potential in predisposing arthralgia, type II cross reactivity secondary to group A streptococcus infection & other comorbidities in treating PCOS.

One of the most common endocrinological disorder affecting women in adolescence is Polycystic Ovarian Syndrome (PCOS). Women suffering from PCOS diagnosed with follicles in ovaries show enlarged reproductive organs with small filled follicles. Unusual bleeding, prolonged menstruation, unwanted hair growth, accumulation of fat and acne are the most common problems experienced by adolescents with PCOS. Nowadays, PCOS is treated successfully with the oral antidiabetic drug, metformin and hormone replacement therapy. Its off-label use is still controversial with unknown mechanisms due to patient risk versus benefit hypothesis by practitioners as they successfully treat PCOS in adolescents with metformin. But in few reported cases metformin has potential to induce back pain and swollen joints less frequently with rare cases of behavior alteration. Penicillin belongs to the beta-lactam antibiotics and is most commonly used to treat rheumatic fever although it has potential to cause allergic reactions affecting 10% of patients who exhibit IgE-mediated immunological reactions. Here, we present a case of a female diagnosed with PCOS who after treatment with metformin for more than two years, reported with hyperuricemia, migraine, neurological pain, severe joint and knee pains on shoulders and legs, and rheumatic fever. After treatment with benzathine benzyl penicillin for rheumatic fever, the patient also exhibited Type IV delayed hypersensitivity reaction.

Cytokine-Induced Acute Inflammatory Monoarticular Arthritis.

Animal models of arthritis enable us to investigate the pathogenesis of the disease and also to evaluate new therapies. Here we describe two different acute inflammatory monoarticular arthritis models (mBSA/IL1ß and mBSA/GM-CSF) providing a more rapid and potentially simplified approach to investigate the pathogenesis.

Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice.

BACKGROUND: Interleukin 1 beta (IL-1beta) plays an important role in a number of chronic and acute inflammatory diseases. To understand the role of IL-1beta in disease processes and develop an in vivo screening system for anti-inflammatory drugs, a transgenic mouse line was generated which incorporated the transgene firefly luciferase gene driven by a 4.5-kb fragment of the human IL-1beta gene promoter. Luciferase gene expression was monitored in live mice under anesthesia using bioluminescence imaging in a number of inflammatory disease models. RESULTS: In a LPS-induced sepsis model, dramatic increase in luciferase activity was observed in the mice. This transgene induction was time dependent and correlated with an increase of endogenous IL-1beta mRNA and pro-IL-1beta protein levels in the mice. In a zymosan-induced arthritis model and an oxazolone-induced skin hypersensitivity reaction model, luciferase expression was locally induced in the zymosan injected knee joint and in the ear with oxazolone application, respectively. Dexamethasone suppressed the expression of luciferase gene both in the acute sepsis model and in the acute arthritis model. CONCLUSION: Our data suggest that the transgenic mice model could be used to study transcriptional regulation of the IL-1beta gene expression in the inflammatory process and evaluation the effect of anti-inflammatory drug in vivo.

[Paradoxic occurrence of symptoms of rheumatic fever after thrombolytic therapy with streptokinase--a case of delayed hypersensitivity?]. / Paradoxes Auftreten von Symptomen des rheumatischen Fiebers nach einer Lysetherapie mit Streptokinase--eine allergische Spätreaktion?

We report the case of a 51-year-old patient with a Paget von Schrötter-Syndrome of the right arm who underwent a successful lysis therapy with 9 x 10(6) IU streptokinase (Streptase) i.v. over 3 days. 36 h after ending the lysis therapy he developed a generalized eczema, which was interpreted as a drug-induced allergic reaction of the arthus type (Coombs III). He received methylprednisolone p.o. with an initial dose of 40 mg, tapered to 0 over 5 days. One day after the efflorent rash the patient developed fever for 12 h (with 38.8 degrees C maximum) and a gonarthritis of the left knee, and 24 h later of both knees. An echocardiogram showed a small pericardial effusion without hemodynamic influence. On the following 2 days a minimal proteinuria of 0.28 and 0.22 g/l was found. Subsequently and after a follow-up of 2 years, the patient was totally free of pathologic clinical and laboratory findings. We interpret this unusual case as a delayed hypersensitivity reaction to streptokinase with a paradoxical occurrence of clinical symptoms formally fulfilling the diagnostic criteria of "rheumatic fever".