Janus kinase inhibitors for treatment of morphea and systemic sclerosis: A literature review.

Morphea and systemic sclerosis (SSc) are rare disorders of connective tissue characterized by increased skin thickness and fibrosis, with current treatment options having variable efficacies, many with limited therapeutic benefit. Janus kinase (JAK) inhibitors have been shown in preclinical studies to inhibit the fibrotic pathway in murine models of systemic sclerosis, by blocking TGF-beta mediated pathway of STAT protein activation. Additionally, case reports of the treatment of morphea and SSc with tofacitinib, a JAK 1/3 inhibitor, have shown improvement in skin sclerosis. Several JAK inhibitors have been developed and utilized in dermatologic and rheumatologic diseases. To date, tofacitinib has been by far the most commonly trialed JAK inhibitor in patients with SSc and morphea. Herein we review the preclinical studies reported in the literature supporting the use and efficacy of JAK inhibitors for the treatment of morphea and the cutaneous manifestations of SSc, as well as discuss the clinical cases published to date illustrating the benefits of JAK inhibitors in disease management. The pathogenesis and mechanism of action will be reviewed as it relates to the process of skin fibrosis in morphea and SSc, along with the murine models illustrating efficacy of JAK inhibitors in fibrotic disease. Based on available preclinical and clinical data as well as consideration of the mechanism of action of JAK inhibitors on the pathway for cutaneous fibrosis, there is promising evidence to support the use and further study of JAK inhibitors in the management of morphea and cutaneous fibrosis in SSc.

Rituximab in autoimmune pemphigoid diseases: Indications, optimized regimens, and practice gaps.

Rituximab is a monoclonal antibody targeting CD20 on B cells with proven efficacy for pemphigus vulgaris, now an FDA-approved indication. Other autoimmune bullous diseases can be challenging to treat and have significant associated morbidity and mortality, but data supporting the use of rituximab in pemphigoid group diseases remain limited. Although rituximab demonstrates efficacy for clinical improvement and remission in pemphigoid, concern for adverse events may also limit the use of this medication. We review the current evidence fo rthe use of rituximab in pemphigoid diseases, pertinent dosing schedules and laboratory monitoring, and the associated common and rare adverse events. Review of the literature to date not only supports consideration of rituximab for treatment of refractory pemphigoid group diseases but also reflects tolerability and an acceptable safety profile.

Scar sarcoidosis following rituximab therapy.

Drug-induced sarcoidosis has been rarely described but it constitutes a potential side effect of immunomodulatory medications. We report a case of rituximab-induced scar sarcoidosis and review similar published cases. Although there is evidence of B-cell dysregulation in the pathogenesis of sarcoidosis, the use of rituximab for this disease needs to be carefully evaluated based on reports of worsening and de novo development of sarcoidosis after rituximab therapy.

Successful treatment of recalcitrant molluscum contagiosum in a stem cell transplant patient with Candida immunotherapy.

Solid organ and stem cell transplant recipients have an increased risk of developing cutaneous infections, which often are refractory to conventional treatment (Euvrard et al., Journal of the American Academy of Dermatology, 2001, 44, 932-939). Molluscum contagiosum, a common self-limited disease primarily affecting children, can be more severe and unresponsive to therapy in transplant patients (Gardner & Ormond, Clinical and Experimental Dermatology, 2006, 31, 452-453). Candida immunotherapy has been widely used for the treatment of warts, and recently its application has been expanded to include treatment of symptomatic molluscum in pediatric patients (Enns & Evans, Pediatric Dermatology, 2011, 28, 254-258; Maronn et al., Pediatric Dermatology, 2008, 25, 189-192). However, to our knowledge there have been no reports in the literature of its utility in the setting of adult transplant or immunocompromised patients. Herein, we report a case of successful treatment of refractory molluscum contagiosum in a stem cell transplant patient with Candida immunotherapy.

Retinoic acid for treatment of systemic sclerosis and morphea: A literature review.

Systemic sclerosis and morphea are connective tissue diseases characterized by tightening, thickening, and hardening of the skin, leading to significant morbidity. Unfortunately, current treatment options have limited efficacy for many patients. Cutaneous manifestations of these diseases arise from excess collagen deposition and fibrosis in the skin, through pathogenic mechanisms which have yet to be extensively detailed at the causal immune and cellular levels. Research elucidating the mechanism of action of retinoic acid on collagen production in the skin and case series highlighting the success of retinoic acid on the skin manifestations of systemic sclerosis and on morphea demonstrate its promise as a treatment. Herein they will briefly review the treatment options for both systemic sclerosis and morphea, and will discuss the potential of retinoic acid as a therapy and the supporting evidence from the literature, highlighting the previously published basic science and clinical studies investigating the role of retinoic acid in the treatment of sclerotic skin diseases.

Concepts in Cancer Modeling: A Brief History.

Modeling, an experimental approach to investigate complex biological systems, has significantly contributed to our understanding of cancer. Although extensive cancer research has been conducted utilizing animal models for elucidating mechanisms and developing therapeutics, the concepts in a good model design and its application have not been well elaborated. In this review, we discuss the theory underlying biological modeling and the process of producing a valuable and relevant animal model. Several renowned examples in the history of cancer research will be used to illustrate how modeling can be translatable to clinical applications. Finally, we will also discuss how the advances in cancer genomics and cancer modeling will influence each other going forward. Cancer Res; 76(20); 5921-5. ©2016 AACR.

Highly selective ruthenium metathesis catalysts for ethenolysis.

N-Aryl,N-alkyl N-heterocyclic carbene (NHC) ruthenium metathesis catalysts are highly selective toward the ethenolysis of methyl oleate, giving selectivity as high as 95% for the kinetic ethenolysis products over the thermodynamic self-metathesis products. The examples described herein represent some of the most selective NHC-based ruthenium catalysts for ethenolysis reactions to date. Furthermore, many of these catalysts show unusual preference and stability toward propagation as a methylidene species and provide good yields and turnover numbers at relatively low catalyst loading (<500 ppm). A catalyst comparison showed that ruthenium complexes bearing sterically hindered NHC substituents afforded greater selectivity and stability and exhibited longer catalyst lifetime during reactions. Comparative analysis of the catalyst preference for kinetic versus thermodynamic product formation was achieved via evaluation of their steady-state conversion in the cross-metathesis reaction of terminal olefins. These results coincided with the observed ethenolysis selectivities, in which the more selective catalysts reach a steady state characterized by lower conversion to cross-metathesis products compared to less selective catalysts, which show higher conversion to cross-metathesis products.

Thermally Stable, Latent Olefin Metathesis Catalysts.

Highly thermally stable N-aryl,N-alkyl N-heterocyclic carbene (NHC) ruthenium catalysts were designed and synthesized for latent olefin metathesis. These catalysts showed excellent latent behavior toward metathesis reactions, whereby the complexes were inactive at ambient temperature and initiated at elevated temperatures, a challenging property to achieve with second generation catalysts. A sterically hindered N-tert-butyl substituent on the NHC ligand of the ruthenium complex was found to induce latent behavior toward cross-metathesis reactions, and exchange of the chloride ligands for iodide ligands was necessary to attain latent behavior during ring-opening metathesis polymerization (ROMP). Iodide-based catalysts showed no reactivity toward ROMP of norbornene-derived monomers at 25 °C, and upon heating to 85 °C gave complete conversion of monomer to polymer in less than 2 hours. All of the complexes were very stable to air, moisture, and elevated temperatures up to at least 90 °C, and exhibited a long catalyst lifetime in solution at elevated temperatures.

Enantioselective epoxide polymerization using a bimetallic cobalt catalyst.

A highly active enantiopure bimetallic cobalt complex was explored for the enantioselective polymerization of a variety of monosubstituted epoxides. The polymerizations were optimized for high rates and stereoselectivity, with s-factors (k(fast)/k(slow)) for most epoxides exceeding 50 and some exceeding 300, well above the threshold for preparative utility of enantiopure epoxides and isotactic polyethers. Values for mm triads of the resulting polymers are typically greater than 95%, with some even surpassing 98%. In addition, the use of a racemic catalyst allowed the preparation of isotactic polyethers in quantitative yields. The thermal properties of these isotactic polyethers are presented, with many polymers exhibiting high T(m) values. This is the first report of the rapid synthesis of a broad range of highly isotactic polyethers via the enantioselective polymerization of racemic epoxides.

Nonproductive events in ring-closing metathesis using ruthenium catalysts.

The relative TONs of productive and nonproductive metathesis reactions of diethyl diallylmalonate are compared for eight different ruthenium-based catalysts. Nonproductive cross metathesis is proposed to involve a chain-carrying ruthenium methylidene. A second more-challenging substrate (dimethyl allylmethylallylmalonate) that forms a trisubstituted olefin product is used to further delineate the effect of catalyst structure on the relative efficiencies of these processes. A steric model is proposed to explain the observed trends.

Isospecific polymerization of racemic epoxides: a catalyst system for the synthesis of highly isotactic polyethers.

A highly active bimetallic cobalt catalyst system is reported for the polymerization of racemic terminal epoxides to yield isotactic polyethers.

Enantioselective polymerization of epoxides: a highly active and selective catalyst for the preparation of stereoregular polyethers and enantiopure epoxides.

A chiral, bimetallic cobalt catalyst was discovered that is highly active and enantioselective for epoxide polymerization. The enantiomerically pure catalyst system exhibits a stereoselectivity factor (s = k(fast)/k(slow)) of 370 for propylene oxide, allowing enantiomerically pure epoxide to be recovered in nearly the maximum theoretical yield. In addition, the racemic catalyst forms highly isotactic poly(propylene oxide) in quantitative yield. The catalyst is active and selective for other epoxides, such as 1-butene oxide, 1-hexene oxide, and styrene oxide.