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Inhibition of multiple JAKs by tofacitinib suggests a high risk for infections and malignancies. Interestingly, clinically observed toxicity is limited, probably attributable to rapid kinetics of action. The most common AEs reported with oral tofacitinib include upper respiratory tract infections, headache, diarrhea, and reactivation of viral infections (particularly herpes zoster). Risk of disseminated disease and serious infections is more with higher dose (10 mg BD) and with concomitant immunomodulators (methotrexate or corticosteroids) necessitating more cautious monitoring.
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Malignancies, most commonly cancers involving the prostate, lungs, breast, and NMSC have been reported in tofacitinib studies, with the risk being comparable to that observed with other targeted immunosuppressive therapies.[11,47] Lymphomas and Epstein Barr virus-associated posttransplant lymphoproliferative disorders have been observed at an increased rate in renal transplant patients treated with tofacitinib and concomitant immunosuppressive medications. Targeted screening with personal and family history of malignancy, including NMSC and other risk factors such as past treatment with UVB, merits consideration in high-risk patients before tofacitinib administration. Long-term studies are warranted to evaluate the specific risk of malignancy induction with oral tofacitinib in cutaneous disorders.
Laboratory derangements may occur. Cytopenias are generally not common with tofacitinib (due to weak JAK2 inhibition), particularly in patients with healthy bone marrow reserves. However, anemia, and fall in red blood cells, neutrophil and lymphocyte counts have been reported in studies of tofacitinib given for RA and UC. Elevations in creatine phosphokinase enzyme and liver enzymes (transaminases) greater than three times the upper limit of normal have been observed in patients treated with tofacitinib. Dyslipidemia with minor elevations in low-density lipoprotein, high-density lipoprotein, and total cholesterol and serum triglyceride levels are well known with this drug. Despite an increased risk of hypertension and dyslipidemia, an increased risk of major adverse cardiovascular events has not been reported. Tofacitinib-induced hyperlipidemia may last for up to 12 weeks followed by stabilization. Persistent hyperlipidemia should be treated as per standard clinical guidelines, e.g., National Cholesterol Educational Program (NCEP). Use of lipid lowering agents such as statins improves the dyslipidemia, although regular monitoring of hepatic enzymes becomes mandatory in such cases.
METHODS. This was a 2-center, open-label, single-arm trial using the pan-JAK inhibitor, tofacitinib citrate, for AA with >50% scalp hair loss, alopecia totalis (AT), and alopecia universalis (AU). Tofacitinib (5 mg) was given twice daily for 3 months. Endpoints included regrowth of scalp hair, as assessed by the severity of alopecia tool (SALT), duration of hair growth after completion of therapy, and disease transcriptome.
CONCLUSIONS. At the dose and duration studied, tofacitinib is a safe and effective treatment for severe AA, though it does not result in a durable response. Transcriptome changes reveal unexpected molecular complexity within the disease.
Two patients dropped out of the trial prior to receiving medication due to inability to attend trial visits. Two additional patients withdrew from the study prior to completing 3 months of tofacitinib citrate.
To generate a signature of early tofacitinib response, a naive, unsupervised hierarchical clustering (HCL) analysis was performed at 8 weeks of treatment using the AA gene signatures (AAGS) derived from previously published work, which are a validated representation of AA pathogenesis and severity (9). This disease signature accurately separated SRs and NRs at 8 weeks (Supplemental Figure 2), indicating that the course of response in this trial followed comparable molecular tracks that have been validated as characterizing AA pathology.
The effect of tofacitinib on the JAK/STAT pathway in AA is evidenced by the downregulation of pSTAT3 in hair follicles during treatment. A recent study of normal murine cycling hair demonstrated that JAK signaling induces a telogen block, preventing the hair from entering anagen phase and that JAK inhibitors induce anagen hair growth similar to a hedgehog pathway agonist (15). Another study demonstrated upregulation of pSTAT1 and pSTAT3 signaling in hair follicles in AA but not normal hair follicles due to IFN-γ signaling (5), supporting the idea that immune dysregulation enforces a similar hair cycle arrest.
Unlike in the murine studies, the data herein show that inhibition of the JAK/STAT pathway by tofacitinib is not entirely predictive of short-term hair growth in AA and reveal a more complex molecular pathogenesis. While shorter duration of current episode of disease is positively associated with response, patients with duration of current episode of disease up to 24 years exhibited a molecular signature similar to those with shorter duration disease. The ALADIN score, previously validated in ruxolitinib-treated patients (5) and in Mackay-Wiggan et al. (16), adequately predicted patient response to ruxolitinib, and it was not able to stratify SRs from NRs to tofacitinib. This is not surprising, as the target specificity of the drugs differs and because there was a predominance of AT and AU patients in this study, rather than patch-stage AA in the ruxolitinib trial, or, alternatively, because our study analyzed patients at 2 months after treatment with tofacitinib, which may not represent a complete response or reversion of gene expression signatures.
Tofacitinib is an inhibitor of Janus kinases, a group of intracellular enzymes involved in signalling pathways that affect hematopoiesis and immune cell function. It is approved by the FDA for treatment of moderate to severe rheumatoid arthritis that responds inadequately to methotrexate or in those who are intolerant to methotrexate.Besides rheumatoid arthritis, tofacitinib has also been studied in clinical trials for the prevention of organ transplant rejection, and is currently under investigation for the treatment of psoriasis. Known adverse effects include nausea and headache as well as more serious immunologic and hematological adverse effects. Tofacitinib is marketed under the brand name Xeljanz by Pfizer.
Note: Fraudulent online pharmacies may attempt to sell an illegal generic version of Xeljanz. These medications may be counterfeit and potentially unsafe. If you purchase medications online, be sure you are buying from a reputable and valid online pharmacy. Ask your health care provider for advice if you are unsure about the online purchase of any medication.
This invention relates to novel amorphous and crystallline forms of 3-(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl-3-oxo-propionitrile mono citrate salt, useful as inhibitors of protein kinases, and to their methods of preparation.
Taking tofacitinib may decrease your ability to fight infection and increase the risk that you will get a serious infection, including severe fungal, bacterial, or viral infections that spread through the body. These infections may need to be treated in a hospital and may cause death. Tell your doctor if you often get any type of infection or if you think you may have any type of infection now. This includes minor infections (such as open cuts or sores), infections that come and go (such as cold sores), and chronic infections that do not go away. Also tell your doctor if you have or have ever had diabetes, human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), a lung disease, or any other condition that affects your immune system. You should also tell your doctor if you live or have ever lived in areas such as the Ohio or Mississippi river valleys where severe fungal infections are more common. Ask your doctor if you are not sure if these infections are common in your area. Tell your doctor if you are taking medications that decrease the activity of the immune system such as the following: abatacept (Orencia); adalimumab (Humira); anakinra (Kineret); azathioprine (Azasan); certolizumab (Cimzia); cyclosporine (Gengraf, Neoral, Sandimmune); etanercept (Enbrel); golimumab (Simponi); infliximab (Remicade); methotrexate (Otrexup, Rasuvo, Trexall); rituximab (Rituxan); steroids including dexamethasone, methylprednisolone (Medrol), prednisolone (Orapred ODT, Prelone), and prednisone (Rayos); tacrolimus (Astagraf, Envarsus XR, Prograf); and tocilizumab (Actemra).
You may already be infected with tuberculosis (TB; a serious lung infection) but not have any symptoms of the disease. In this case, using tofacitinib may make your infection more serious and cause you to develop symptoms. Your doctor will perform a skin test to see if you have an inactive TB infection before you begin your treatment with tofacitinib. If necessary, your doctor will give you medication to treat this infection before you start using tofacitinib. Tell your doctor if you have or have ever had TB, if you have lived in or visited a country where TB is common, or if you have been around someone who has TB. If you have any of the following symptoms of TB, or if you develop any of these symptoms during your treatment, call your doctor immediately: cough, coughing up bloody mucus, weight loss, loss of muscle tone, or fever.
Taking tofacitinib may cause serious or life-threatening heart problems, such as a heart attack or stroke, or serious or life-threatening blood clots in the legs, arms, lungs, or in the arteries during your treatment. Tell your doctor if you smoke or if you have ever smoked. Also tell your doctor if have or have ever had a heart attack or other heart problems; a stroke; a blood clot in your legs, arms, or lungs, or in the arteries; high cholesterol; high blood pressure; or diabetes. If you experience any of the following symptoms during your treatment, call your doctor immediately or get emergency medical treatment: pain in the chest, arms, back, neck, jaw, or stomach; breaking out in cold sweat; feeling light-headed; dizziness; numbness or weakness in face, arm, or legs; slow or difficult speech; sudden shortness of breath or difficulty breathing; swelling of a leg or arm; leg pain; redness, discoloration, or warmth in the legs or arms. 041b061a72