Jivko Kamarachev

Transient Efficacy of Tofacitinib in Alopecia Areata Universalis

Alopecia areata is a common autoimmune disorder that targets hair follicles. Swarms of lymphocytes surround the basis of the follicles, inducing loss of pigmented terminal hair and subsequently inhibit further hair growth. Depending on the extent of involvement, alopecia areata can be associated with a dramatic reduction of quality of life. Currently, no targeted treatment option is available, and topical immune therapies or immunosuppressive drugs are typically used with mixed success. Recently, several cases of alopecia areata responding to Janus kinase inhibitors were published. Here, we report on a businessman with alopecia areata universalis who was treated with tofacitinib. We observed initial signs of hair regrowth in the same timeframe as previously reported, but efficacy quickly waned again, leading to renewed effluvium. Thus, even though tofacitinib and ruxolitinib are a promising new treatment option, we have yet to learn more about their potential role in each particular patients individual treatment strategy.

Disseminated Herpes Zoster Mimicking Rheumatoid Vasculitis in a Rheumatoid Arthritis Patient on Etanercept

Tumor necrosis factor-α (TNFα)-blocking agents are immunomodulating agents introduced for treatment of a variety of chronic inflammatory disease conditions. Adverse effects include an increased incidence of infections. Clinically, these infections often have atypical presentations that may hamper prompt diagnosis. In our report of a patient on etanercept therapy for rheumatoid arthritis, the correct diagnosis was delayed because disseminated herpes zoster was clinically mimicking vasculitis. Initially assuming rheumatoid vasculitis, immunosuppression was increased, resulting in worsening of skin lesions. Only an extended work-up, including a skin biopsy and viral cultures, established the correct diagnosis. Management of varicella zoster virus (VZV) infection primarily focuses on early initiation of antiviral therapy to control VZV replication. Therapy with intravenous acyclovir followed by oral valacyclovir allowed complete resolution of acute skin changes. In immunosuppressed patients, the possibility of infection with atypical presentation must always be kept in mind, and that this might mimic other disease conditions. Broad differential diagnosis and an extended diagnostic workup help in establishing the correct diagnosis.

Severe Sweet's Syndrome with Elevated Cutaneous Interleukin-1β after Azathioprine Exposure: Case Report and Review of the Literature.

Sweets syndrome (SS) is a dermatosis with systemic symptoms characterized by tender, red nodules or papules, occasionally covered with vesicles, pustules or bullae, usually affecting the upper limbs, face and neck. SS is frequently observed in patients with leukemia or connective tissue diseases, while it is rather seldom in patients with inflammatory bowel disease. The exact pathogenesis of SS is only partially understood. We report the case of a 50-year-old patient with indeterminate colitis, presenting with a febrile diffuse papulopustular and necrotizing skin eruption that healed with significant scarring and appeared 14 days after onset of treatment with azathioprine. Histological examination revealed the presence of features typical of SS, gene expression analysis very high levels of interleukin-1β (IL-1β) mRNA in lesional skin, and immunohistochemistry high levels of IL-1β at the protein level. SS associated with azathioprine is being increasingly reported and is reviewed herein.

Expression of programmed death-1 (CD279) in primary cutaneous B-cell lymphomas with correlation to lymphoma entities and biological behaviour.

Programmed death‐1 (PD‐1/CD279) is a cell‐surface protein expressed in activated T cells and a subset of T lymphocytes including follicular helper T cells (TFH). The interaction between PD‐1 and its ligands plays a role in immune response and evasion of malignancies. In nodal follicular lymphoma, the number of intratumoral PD‐1‐positive lymphocytes is associated with overall survival.

Treating insect-bite hypersensitivity in horses with active vaccination against IL-5

Background Insect‐bite hypersensitivity is the most common allergic dermatitis in horses. Excoriated skin lesions are typical symptoms of this seasonal and refractory chronic disease. On a cellular level, the skin lesions are characterized by massive eosinophil infiltration caused by an underlying allergic response. Objective To target these cells and treat disease, we developed a therapeutic vaccine against equine IL‐5 (eIL‐5), the master regulator of eosinophils. Methods The vaccine consisted of eIL‐5 covalently linked to a virus‐like particle derived from cucumber mosaic virus containing the tetanus toxoid universal T‐cell epitope tt830‐843 (CMVTT). Thirty‐four Icelandic horses were recruited and immunized with 400 &mgr;g of eIL‐5–CMVTT formulated in PBS without adjuvant (19 horses) or PBS alone (15 horses). Results The vaccine was well tolerated and did not reveal any safety concerns but was able to induce anti–eIL‐5 autoantibody titers in 17 of 19 horses. This resulted in a statistically significant reduction in clinical lesion scores when compared with previous season levels, as well as levels in placebo‐treated horses. Protection required a minimal threshold of anti–eIL‐5 antibodies. Clinical improvement by disease scoring showed that 47% and 21% of vaccinated horses reached 50% and 75% improvement, respectively. In the placebo group no horse reached 75% improvement, and only 13% reached 50% improvement. Conclusion Our therapeutic vaccine inducing autoantibodies against self IL‐5 brings biologics to horses, is the first successful immunotherapeutic approach targeting a chronic disease in horses, and might facilitate development of a similar vaccine against IL‐5 in human subjects. Graphical abstract Figure. No Caption available.

Pyogenic granuloma in patients treated with selective BRAF inhibitors: another manifestation of paradoxical pathway activation

Cutaneous toxicities under therapy with selective BRAF inhibitors such as vemurafenib or encorafenib (LGX818) are frequent, including plantar hyperkeratosis, squamous cell carcinoma, and second primary melanoma. Pyogenic granuloma is a benign, rapidly growing, eruptive hemangioma that often bleeds and ulcerates. Common causes are mechanical trauma and cast immobilization, as well as multiple drugs such as retinoids and antineoplastic agents. However, the development of pyogenic granuloma under treatment with encorafenib (LGX818) has not yet been reported. These three cases might be further examples for paradoxical activation of the mitogen-activated protein kinase pathway. We report three male patients with metastatic BRAFV600E-mutated melanoma who developed pyogenic granulomas 16, 10, and 12 weeks after treatment initiation with the selective BRAF inhibitors vemurafenib or encorafenib (LGX818). Except for one patient receiving retinoids, the clinical history for other frequent causes of pyogenic granuloma was negative. Pyogenic granulomas are not listed in the drugs investigator brochure but seem to be associated with selective BRAF inhibitors and might be a cutaneous phenomenon of paradoxical mitogen-activated protein kinase pathway activation. This correlation has to be confirmed by further observations.

Efficacy and safety of oral alitretinoin in severe oral lichen planus – results of a prospective pilot study

Patients with severe oral lichen planus refractory to standard topical treatment currently have limited options of therapy suitable for long‐term use. Oral alitretinoin (9‐cis retinoic acid) was never systematically investigated in clinical trials, although case reports suggest its possible efficacy.

Collision tumors: CAMEL, METRO and other acronyms.

We describe two exceptional collision tumors, namely: a 63‐year‐old woman revealing a melanocytic tumor within a trichoblastoma and a 71‐year‐old woman with a squamous cell carcinoma colonized by dendritic cells of a melanoma. Both neoplasms showed two different tumor components with intimate relationship.

TLR4 as a negative regulator of keratinocyte proliferation

TLR4 is an innate immune receptor with expression in human skin, keratinocytes as well as squamous cell carcinoma (SCC) of the skin. In the present study we investigate the role of TLR4 as a negative regulator of keratinocyte proliferation. We present here that the expression of TLR4 increased with the differentiation of cultured keratinocytes in a passage-dependent manner or under calcium-rich conditions. Moreover, the down-regulation of TLR4 by specific knockdown increased the proliferation of HaCaT keratinocytes in vitro. In addition, subcutaneously injected HaCaT keratinocytes with shTLR4 formed growing tumors in nude mice. In contrast, we observed lower proliferation and increased migration in vitro of the SCC13 cell line stably overexpressing TLR4 in comparison to SCC13 TLR4 negative cells. In vivo, SCC13 TLR4-overexpressing tumors showed delayed growth in comparison to TLR4 negative tumors. The overexpression of TLR4 in SCC13 tumor cells was followed by phosphorylation of ERK1/2 and JNK and increased expression of ATF3. In gene expression arrays, the overexpression of TLR4 in tumor cells correlated with gene expression of ATF-3, IL-6, CDH13, CXCL-1 and TFPI. In summary, TLR4 negatively regulates the proliferation of keratinocytes and its overexpression reduces tumor growth of SCC cells.

New Onset of Kaposi Sarcoma in a Human Immunodeficiency Virus-1-Infected Homosexual Man, Despite Early Antiretroviral Treatment, Sustained Viral Suppression, and Immune Restoration

This is a rare case of new onset Kaposi sarcoma in a man infected with human immunodeficiency virus (HIV) and receiving antiretroviral treatment since primary HIV infection, with normal CD4+ cell count and suppressed viral load. The presentation questions the general understanding of Kaposi sarcoma as an acquired immune deficiency syndrome-defining disease occurring predominantly in severely immunocompromised patients infected with HIV.