Tofacitinib (Xeljanz)

Number: 0839

Policy

Note: REQUIRES PRECERTIFICATION.Footnotes for Requirement of Precertification***

Note: There are several brands of targeted immune modulators on the market. There is a lack of reliable evidence that any one brand of targeted immune modulator is superior to other brands for medically necessary indications.  Enbrel (etanercept), Entyvio (vedolizumab), Inflectra (infliximab-dyyb), Otezla (apremilast), Remicade (infliximab), Renflexis (infliximab-abda), Simponi (golimumab), Simponi Aria (golimumab intravenous), Stelara (ustekinumab), Tremfya (guselkumab), Xeljanz and Xeljanz XR (tofacitinib) brands of targeted immune modulators ("least cost brands of targeted immune modulators") are less costly to Aetna.  Consequently, because Actemra (tocilizumab), Humira (adalimumab), Kineret (anakinra), Orencia (abatacept), Rituxan (rituximab), and Tysabri (natalizumab) brands of targeted immune modulators are more costly than the least cost brands of targeted immune modulators, and least cost brands of targeted immune modulators are at least as likely to produce equivalent therapeutic results, these brands of targeted immune modulator will be considered medically necessary only if the member has a contraindication, intolerance or ineffective response to the following numbers of trials of least cost brands of targeted immune modulators by indication:

• Ankylosing spondylitis – two least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria)
• Crohn’s disease – one least cost brand (not including Renflexis) (i.e., Entyvio, Inflectra, Remicade, Stelara)
• Juvenile idiopathic arthritis – trial of Enbrel (etanercept)
• Plaque psoriasis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Stelara, Tremfya)
• Psoriatic arthritis – three least cost brands (i.e., Enbrel, Inflectra, Otezla, Remicade, Renflexis, Simponi, Simponi Aria, Stelara, Xeljanz, Xeljanz XR)
• Rheumatoid arthritis – three least cost brands (i.e., Enbrel, Inflectra, Remicade, Renflexis, Simponi, Simponi Aria, Xeljanz/Xeljanz XR)
• Ulcerative colitis – one least cost brand (not incl uding Renflexis) (i.e., Entyvio, Inflectra, Remicade, Simponi, Xeljanz)

Note: Cimzia (certolizumab), Cosentyx (secukinumab), Ilaris (canakinumab), Ilumya (tildrakizumab-asmn), Kevzara (sarilumab), Olumiant (baricitinib), Siliq (brodalumab), and Taltz (ixekizumab) brands of targeted immune modulators do not require a trial of a least cost brand of targeted immune modulator; there may, however, be a higher copayment where these brands are covered under pharmacy plans with a tiered formulary. Please check benefit plan descriptions. If the least costly targeted immune modulators do not have the labeled indication (see Appendix), then Aetna considers medically necessary another brand of targeted immune modulator that has the required labeling indication. Also note that Renflexis is not a least cost brand for Crohn’s disease and ulcerative colitis indications.

Aetna considers tofacitinib (Xeljanz and Xeljanz XR), medically necessary for the following indications, where the member has a documented negative TB test (which can include a tuberculosis skin test (PPD), an interferon-release assay (IGRA), or a chest x-ray)Footnotes* within 6 months of initiating therapy for persons who are naive to biologics, and repeated yearly for members with risk factorsFootnotes** for TB that are continuing therapy with biologics:

• Treatment of adults with moderately to severely active rheumatoid arthritis (RA), who have had an ineffective response to methotrexate, or if methotrexate is contraindicated or not tolerated, has had an ineffective response to another non-biologic disease-modifying anti-rheumatic drug (conventional DMARD) (i.e. azathioprine, hydroxychloroquine, leflunomide, sulfasalazine). or
  
  
• Treatment of adult members with active psoriatic arthritis (PsA) who meet criteria in CPB 0658 - Psoriasis and Psoriatic Arthritis: Targeted Immune Modulators; or
  
  
• Treatment of adults with moderately to severely active ulcerative colitis (UC) who meet the following criteria (Xeljanz immediate release (IR) formulation only, not extended release (not Xeljanz XR):
  
  
  • Member is hospitalized with fulminant UC (i.e., severe UC with more than 10 stools per day, continuous bleeding, abdominal pain, distension, and acute, severe toxic symptoms including fever and anorexia; or
  • Member has active moderate to severe UC and meets all of the following criteria:
     
    • Refractory to, or requires continuous immunosuppression with corticosteroids (e.g., methylprednisolone, prednisone) at a dose equivalent to prednisone 40 to 60 mg/day for 30 days (oral therapy) or 10 days (IV therapy); and
    • Treatment with 5-aminosalicylic acid agents (e.g., balsalazide, mesalamine, sulfasalazine) was ineffective, not tolerated, or is contraindicated; and
    • Treatment with immunosuppressants (e.g. azathioprine, 6-mercaptopurine) was ineffective, not tolerated, or is contraindicated.
       
• Aetna considers tofacitinib in combination with a biologic DMARDs (e.g., adalimumab, etanercept, apremilast (Otezla)) or potent immunosuppressants (e.g., azathioprine and cyclosporine) for the treatment of RA experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers tofacitinib experimental and investigational for the following diseases/conditions (not an all-inclusive list) because its effectiveness for these indications has not been established:

• Alopecia
• Ankylosing spondylitis
• Atopic dermatitis
• Autoimmune lymphoproliferative syndrome
• Crohn's disease
• Corneal inflammation
• Dry eye disease
• Juvenile idiopathic arthritis
• Lymphadenopathy
• Mast cell activation syndrome
• Prevention of organ transplant rejection
• Psoriasis (including plaque psoriasis)
• Spondyloarthritis
• Systemic lupus erythematosus
• Vitiligo

Background

Tofacitinib is an inhibitor of the enzyme Janus kinase 3 (JAK3), which means that it interferes with the JAK-STAT signaling pathway that plays an important role in the pathogenesis of RA. 

JAKs are intracellular enzymes which transmit signals arising from cytokine or growth factor‐receptor interactions on the cellular membrane to influence cellular processes of hematopoiesis and immune cell function. Within the signaling pathway, JAKs phosphorylate and activate Signal Transducers and Activators of Transcription (STATs) which modulate intracellular activity including gene expression. Tofacitinib modulates the signaling pathway at the point of JAKs, preventing the phosphorylation and activation of STATs. JAK enzymes transmit cytokine signaling through pairing of JAKs (e.g., JAK1/JAK3, JAK1/JAK2, JAK1/TyK2, JAK2/JAK2). Tofacitinib inhibited the in vitro activities of JAK1/JAK2, JAK1/JAK3, and JAK2/JAK2 combinations with IC50 of 406, 56, and 1377 nM, respectively. However, the relevance of specific JAK combinations to therapeutic effectiveness is not known.

Waldmann (2013) noted that IL-15 has a pivotal role in life and death of natural killer (NK) and CD8 memory T cells.  IL-15 signals through a hetero-trimeric receptor involving the common gamma chain (γc) shared with IL-2, IL-4, IL-7, IL-9, and IL-21, IL-2/IL-15 receptor β (IL-15Rβ) shared with IL-2 and a private IL-15Rα subunit.  IFN- or CD40 ligand-stimulated dendritic cells coordinately express IL-15 and IL-15Rα.  Cell surface IL-15Rα presents IL-15 in trans to cells that express IL-2/IL-15Rβ and γc.  IL-15 is being used to treat patients with metastatic malignancy.  However, IL-15 is an inflammatory cytokine involved in immunological memory including that to self, thereby playing a role in autoimmune diseases.  These insights provided the scientific basis for clinical strategies directed toward diminishing IL-15 action.  Dysregulated IL-15 expression was demonstrated in patients with rheumatoid arthritis, inflammatory bowel disease, psoriasis, celiac disease, and alopecia areata.  The monoclonal antibody Hu-Mik-β-1 targets the cytokine receptor subunit IL-2/IL-15Rβ (CD122), blocks IL-15 transpresentation, and is being used in clinical trials in patients with autoimmune diseases.  In parallel, clinical trials have been initiated involving the Jak2/3 (Janus kinase-2/3) inhibitor tofacitinib and Jak1/2 inhibitor ruxolitinib to block IL-15 signaling.

Rheumatoid Arthritis

Currently available therapeutic options for rheumatoid arthritis (RA) entail disease-modifying anti-rheumatic drugs (DMARDs; e.g., anti-malarials, cyclosporine, gold compounds, methotrexate, or sulfasalazine), and biologic agents (e.g., adalimumab, abatacept, anakinra, etanercept, infliximab, rituximab, and tocilizumab).  However, these treatments often fail to adequately prevent disease progression. 

On November 6, 2012, the Food and Drug Administration (FDA) approved tofacitinib (Xeljanz) for the treatment of adults with moderately-to-severely active RA who have had an inadequate response to, or who are intolerant of, MTX. The FDA approved tofacitinib with a Risk Evaluation and Mitigation Strategy (REMS), which consists of a Medication Guide advising patients about important safety information and a communication plan to inform health care providers about the serious risks associated with tofacitinib. Tofacitinib has been evaluated in phase II and phase III studies, as both monotherapy and in combination with methotrexate (MTX) and other DMARDs, and demonstrated improvements in the signs and symptoms of RA, patient health, physical functioning as well as quality of life, while having a manageable safety profile (de Lartigue, 2012). Xeljanz (tofacitinib) may be used as monotherapy or in combination with methotrexate or other non‐biologic disease modifying antirheumatic drugs (DMARDs). Xeljanz (tofacitinib) should not be used in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine.

In a 12-week, phase II, double-blind study, Tanaka et al (2011) compared the efficacy, safety, and tolerability of 4 doses of oral tofacitinib with placebo in Japanese patients with active RA receiving stable background MTX who had an inadequate response to MTX alone.  A total of 140 patients were randomized to receive tofacitinib 1, 3, 5, and 10 mg twice-daily or placebo in this study.  All patients remained on background MTX.  Efficacy and safety were assessed at weeks 1, 2, 4, 8, and 12.  The primary efficacy end point was the American College of Rheumatology 20 % improvement criteria (ACR20) response rate at week 12.  ACR20 response rates at week 12 were significant (p < 0.0001) for all tofacitinib treatment groups: 1 mg twice-daily, 64.3 %; 3 mg twice-daily, 77.8 %; 5 mg twice-daily, 96.3 %; and 10 mg twice-daily, 80.8 % versus placebo, 14.3 %.  A significant dose-response relationship for the ACR20 was observed (p < 0.0001).  Low disease activity was achieved by 72.7 % of patients with high baseline disease activity for tofacitinib 10 mg twice-daily at week 12 (p < 0.0001).  Significant improvements in the ACR50, ACR70, Health Assessment Questionnaire Disability Index (HAQ-DI) score, and 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein (DAS28-3[CRP]) were also reported.  The most commonly reported adverse events (AEs) were naso-pharyngitis (n = 13) and increased alanine aminotransferase (n = 12) and aspartate aminotransferase (n = 9) levels.  These AEs were mild or moderate in severity.  Serious AEs were reported by 5 patients; no deaths occurred.  The authors concluded that in Japanese patients with active RA with an inadequate response to MTX, tofacitinib in combination with MTX over 12 weeks was effective and had a manageable safety profile.

In a 24-week, double-blind, phase IIb study, Fleischmann et al (2012a) compared the efficacy, safety, and tolerability of 5 doses of oral tofacitinib or adalimumab monotherapy with placebo for the treatment of active RA in patients with an inadequate response to DMARDs.  Patients with RA (n = 384) were randomized to receive placebo, tofacitinib at 1, 3, 5, 10, or 15 mg administered orally twice-daily, or adalimumab at 40 mg injected subcutaneously every 2 weeks (total of 6 injections) followed by oral tofacitinib at 5 mg twice-daily for 12 weeks.  The primary end point was the responder rate according to ACR20 at week 12.  Treatment with tofacitinib at a dose of greater than or equal to 3 mg twice-daily resulted in a rapid response with significant efficacy when compared to placebo, as indicated by the primary end point (ACR20 response at week 12), achieved in 39.2 % (3 mg; p ≤ 0.05), 59.2 % (5 mg; p < 0.0001), 70.5 % (10 mg; p < 0.0001), and 71.9 % (15 mg; p < 0.0001) in the tofacitinib group and 35.9 % of patients in the adalimumab group (p = 0.105), compared with 22.0 % of patients receiving placebo.  Improvements were sustained at week 24, according to the ACR20, ACR50, and ACR70 response rates as well as classifications of remission according to the 3-variable Disease Activity Score in 28 joints (DAS28) using C-reactive protein (DAS28-3[CRP]) and the 4-variable DAS28 using the erythrocyte sedimentation rate (DAS28-4[ESR]).  The most common treatment-related AEs in patients across all tofacitinib treatment arms (n = 272) were urinary tract infection (7.7 %), diarrhea (4.8 %), headache (4.8 %), and bronchitis (4.8 %).  The authors concluded that tofacitinib monotherapy at greater than or equal to 3 mg twice-daily was effective in the treatment of patients with active RA over 24 weeks and demonstrated a manageable safety profile.

In a 24-week, double-blind, phase IIb study, Kremer et al (2012) compared the efficacy, safety, and tolerability of 6 doses of oral tofacitinib with placebo for the treatment of active RA in patients receiving a stable background regimen of MTX who have an inadequate response to MTX monotherapy.  Patients with active RA (n = 507) were randomized to receive placebo or tofacitinib (20 mg/day, 1 mg twice-daily, 3 mg twice-daily, 5 mg twice-daily, 10 mg twice-daily, or 15 mg twice-daily).  All patients continued to receive a stable dosage of MTX.  The primary end point was the ACR20 response rate at week 12.  At week 12, ACR20 response rates for patients receiving all tofacitinib dosages greater than or equal to 3 mg twice-daily (52.9 % for 3 mg twice-daily, 50.7 % for 5 mg twice-daily, 58.1 % for 10 mg twice-daily, 56.0 % for 15 mg twice-daily, and 53.8 % for 20 mg/day) were significantly (p ≤ 0.05) greater than those for placebo (33.3 %).  Improvements were sustained at week 24 for the ACR20, ACR50, and ACR70 responses, scores for the HAQ-DI scores, the DAS28-3[CRP], and a 3-variable DAS28-3[CRP] of less than 2.6.  The most common treatment-related AEs occurring in greater than 10 % of patients in any tofacitinib group were diarrhea, upper respiratory tract infection, and headache; 21 patients (4.1 %) experienced serious AEs.  Sporadic increases in transaminase levels; increases in cholesterol and serum creatinine levels; and decreases in neutrophil and hemoglobin levels were observed.  The authors concluded that in patients with active RA in whom the response to MTX has been inadequate, the addition of tofacitinib at a dosage greater than or equal to 3 mg twice-daily showed sustained efficacy and a manageable safety profile over 24 weeks.

In a phase III, double-blind, placebo-controlled, parallel-group, 6-month study, (Fleischmann et al, 2012b), a total of 611 patients were randomly assigned in a 4:4:1:1 ratio to 5 mg of tofacitinib twice-daily, 10 mg of tofacitinib twice-daily, placebo for 3 months followed by 5 mg of tofacitinib twice-daily, or placebo for 3 months followed by 10 mg of tofacitinib twice-daily.  The primary end points, assessed at month 3, were the percentage of patients with at least a 20 % improvement in the ACR 20, the change from baseline in HAQ-DI scores (which ranged from 0 to 3, with higher scores indicating greater disability), and the percentage of patients with a DAS28-joint counts based on DAS28-4[ESR] of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating more disease activity).  At month 3, a higher percentage of patients in the tofacitinib groups than in the placebo groups met the criteria for an ACR 20 response (59.8 % in the 5-mg tofacitinib group and 65.7 % in the 10-mg tofacitinib group versus 26.7 % in the combined placebo groups, p < 0.001 for both comparisons).  The reductions from baseline in HAQ-DI scores were greater in the 5-mg and 10-mg tofacitinib groups than in the placebo groups (-0.50 and -0.57 points, respectively, versus -0.19 points; p < 0.001).  The percentage of patients with a DAS28-4(ESR) of less than 2.6 was not significantly higher with tofacitinib than with placebo (5.6 % and 8.7 % in the 5-mg and 10-mg tofacitinib groups, respectively, and 4.4 % with placebo; p = 0.62 and p = 0.10 for the two comparisons).  Serious infections developed in 6 patients who were receiving tofacitinib.  Common AEs were headache and upper respiratory tract infection.  Tofacitinib treatment was associated with elevations in low-density lipoprotein cholesterol levels and reductions in neutrophil counts.  The authors concluded that in patients with active RA, tofacitinib monotherapy was associated with reductions in signs and symptoms of RA and improvement in physical function.

van Vollenhoven et al (2012) compared tofacitinib and adalimumab in the treatment of RA.  In this 12-month, phase III clinical trial, a total of 717 patients who were receiving stable doses of MTX were randomly assigned to 5 mg of tofacitinib twice-daily, 10 mg of tofacitinib twice-daily, 40 mg of adalimumab once every 2 weeks, or placebo.  At month 3, patients in the placebo group who did not have a 20 % reduction from baseline in the number of swollen and tender joints were switched in a blinded fashion to either 5 mg or 10 mg of tofacitinib twice-daily; at month 6, all patients still receiving placebo were switched to tofacitinib in a blinded fashion.  The 3 primary outcome measures were a 20 % improvement at month 6 in the ACR 20; the change from baseline to month 3 in the score on the HAQ-DI (which ranged from 0 to 3, with higher scores indicating greater disability); and the percentage of patients at month 6 who had a DAS28-4[ESR] of less than 2.6 (with scores ranging from 0 to 9.4 and higher scores indicating greater disease activity).  At month 6, ACR 20 response rates were higher among patients receiving 5 mg or 10 mg of tofacitinib (51.5 % and 52.6 %, respectively) and among those receiving adalimumab (47.2 %) than among those receiving placebo (28.3 %) (p < 0.001 for all comparisons).  There were also greater reductions in the HAQ-DI score at month 3 and higher percentages of patients with a DAS28-4(ESR) below 2.6 at month 6 in the active-treatment groups than in the placebo group.  Adverse events occurred more frequently with tofacitinib than with placebo, and pulmonary tuberculosis developed in 2 patients in the 10-mg tofacitinib group.  Tofacitinib was associated with an increase in both low-density and high-density lipoprotein cholesterol levels and with reductions in neutrophil counts.  The authors concluded that in patients with RA receiving background MTX, tofacitinib was significantly superior to placebo and was numerically similar to adalimumab in efficacy.

To study the long-term effects of tofacitinib on heart disease, cancer, and serious infections, the FDA is requiring a post-marketing study that will evaluate 2 doses of tofacitinib and include a group of patients on another approved treatment to serve as a comparison.  The use of tofacitinib was associated with an increased risk of serious infections, including opportunistic infections, tuberculosis, cancers and lymphoma.  The most common AEs in clinical trials were upper respiratory tract infections, headache, diarrhea, and inflammation of the nasal passage and the upper part of the pharynx.  According to the Prescribing Information of Xeljanz, it may be used as monotherapy or in combination with MTX or other non-biologic DMARDs.  Furthermore, Xeljanz should not be used in combination with biologic DMARDs (such as Humira, Enbrel, Remicade, Cimzia, Simponi, Actemra, Orencia, and Stelara) or potent immunosuppressants such as azathioprine and cyclosporine.

Patients treated with Xeljanz are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Reported infections include:

• Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before Xeljanz use and during therapy. Treatment for latent infection should be initiated prior to Xeljanz use.
• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
• Bacterial, viral, and other infections due to opportunistic pathogens.

Lymphoma and other malignancies have been observed in patients treated with Xeljanz. Epstein Barr Virus associated post‐transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with Xeljanz and concomitant immunosuppressive medications.

Warnings and Precautions include:

• Gastrointestinal perforations‐ Use with caution in patients that may be at increased risk.
• Laboratory monitoring‐ Recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids.
• Immunizations‐ Live vaccines should not be given concurrently with Xeljanz.
• Severe hepatic impairment‐ Not recommended.
• Serious infections ‐ The most common serious infections reported with Xeljanz included pneumonia, cellulitis, herpes zoster, urinary tract infection, and diverticulitis. Avoid use of Xeljanz in patients with an active, serious infection, including localized infections.
• Viral reactivation ‐ Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting Xeljanz.

Tofacitinib is available as Xeljanz 5 mg tablets and as Xeljanz XR 11 mg tablets. The recommended dose of Xeljanz (tofacitinib) is 5 mg twice daily, and the recommended dose of Xeljanz XR is once daily.

Xeljanz dosage should be reduced to 5 mg once daily in patients:

• With moderate or severe renal insufficiency
• With moderate to severe hepatic impairment
• Receiving potent inhibitors of CYP3A4 (e.g. ketoconazole)
• Receiving one or more concomitant medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 (e.g. fluconazole).

American College of Rheumatology (ACR) Recommendations (Singh, et al., 2012):

• If a patient has moderate or high disease activity after 3 months of anti‐TNF biologic therapy and this is due to a lack or loss of benefit, switching to another anti‐TNF biologic or a non‐TNF biologic is recommended (level of evidence B and C).
• If a patient has high disease activity after failing an anti‐TNF biologic because of a serious adverse event, switch to a non‐TNF biologic (level of evidence C).
• If a patient has moderate or high disease activity after failing an anti‐TNF biologic because of a non‐serious adverse event, switch to another anti‐TNF biologic or a non‐TNF biologic (level of evidence B and C).
• If a patient has moderate or high disease activity after failing a non‐TNF biologic because of an adverse event (serious or non‐serious), switch to another non‐TNF biologic or an anti‐TNF biologic (level of evidence C).
  
  

The American College of Rheumatology (ACR) conducted a systematic review to synthesize the evidence for the benefits and harms of various treatment options. Their goal was to develop evidence-based, pharmacologic treatment guideline for rheumatoid arthritis. The 2015 American College of Rheumatology Guidelines for the Treatment of Rheumatoid Arthritis provided “strong” recommendations for established RA and symptomatic early RA.

For established RA, the guidelines state “if the disease activity is low, in patients who have never taken a DMARD, the recommendation is to use DMARD monotherapy (methotrexate preferred) over TNFi”. “If disease activity remains moderate or high despite DMARD monotherapy, the recommendation is to use combination traditional [conventional] DMARDs or add a TNFi or a non-TNF biologic or tofacitinib (all choices with or without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. Recommendations for patients with symptomatic early RA state that “if disease activity is low, in patients who have never taken a DMARD, use DMARD monotherapy (methotrexate preferred) over double or triple therapy”.  “If disease activity remains moderate or high despite DMARD monotherapy (with our without glucocorticoids), use combination DMARDs or a TNFi or a non-TNF biologic (all choices with our without methotrexate, in no particular order of preference), rather than continuing DMARD monotherapy alone”. A strong recommendation means that the panel was confident that the desirable effects of following the recommendation outweigh the undesirable effects (or vice versa), so the course of action would apply to most patients, and only a small proportion would not want to follow the recommendation (Singh et al., 2016).

Psoriatic Arthritis

Gan and colleagues (2013) stated that psoriatic arthritis affects approximately 6 to 42 % of patients with psoriasis.  It is useful for physicians or dermatologists managing psoriasis patients to be aware of how to concurrently manage the joint manifestations, as it is preferable and convenient to use a single agent in such patients.  However, only certain therapies are effective for both.  Systemic agents, which can be used for both skin and joint manifestations, include methotrexate and cyclosporine.  For the group of biologic agents, the tumor necrosis factor inhibitors such as adalimumab, certolizumab, etanercept, golimumab, and infliximab are effective.  Ustekinumab is a more recently developed agent belonging to the group of anti-IL-12p40 antibodies and has been shown to be effective.  Newer drugs in the treatment armamentarium that have shown efficacy for both psoriasis and psoriatic arthritis consist of the anti-IL-17 agent, secukinumab, and a phosphodiesterase-4 inhibitor, apremilast.  The other anti-IL-17 agents, ixekizumab and brodalumab, as well as the oral JAK inhibitor, tofacitinib, have very limited but promising data.

Ulcerative Colitis

Sandborn et al (2017) stated tofacitinib, an oral, small-molecule Janus kinase inhibitor, was shown to have potential efficacy as induction therapy for ulcerative colitis in a phase 2 trial. The authors further evaluated the efficacy of tofacitinib as induction and maintenance therapy in three phase 3, randomized, double-blind, placebo-controlled trials of tofacitinib therapy in adults with ulcerative colitis. In the OCTAVE Induction 1 and 2 trials, 598 and 541 patients, respectively, who had moderately to severely active ulcerative colitis despite previous conventional therapy or therapy with a tumor necrosis factor antagonist were randomly assigned to receive induction therapy with tofacitinib (10 mg twice daily) or placebo for 8 weeks. The primary end point was remission at 8 weeks. In the maintenance trial (OCTAVE Sustain), 593 patients who had a clinical response to induction therapy were randomly assigned to receive maintenance therapy with tofacitinib (either 5 mg or 10 mg twice daily) or placebo for 52 weeks. The primary end point was remission at 52 weeks.

In the OCTAVE Induction 1 trial, remission at 8 weeks occurred in 18.5% of the patients in the tofacitinib group versus 8.2% in the placebo group (P=0.007); in the OCTAVE Induction 2 trial, remission occurred in 16.6% versus 3.6% (P<0.001). In the OCTAVE Sustain trial, remission at 52 weeks occurred in 34.3% of the patients in the 5-mg tofacitinib group and 40.6% in the 10-mg tofacitinib group versus 11.1% in the placebo group (P<0.001 for both comparisons with placebo). In the OCTAVE Induction 1 and 2 trials, the rates of overall infection and serious infection were higher with tofacitinib than with placebo. In the OCTAVE Sustain trial, the rate of serious infection was similar across the three treatment groups, and the rates of overall infection and herpes zoster infection were higher with tofacitinib than with placebo. Across all three trials, adjudicated nonmelanoma skin cancer occurred in five patients who received tofacitinib and in one who received placebo, and adjudicated cardiovascular events occurred in five who received tofacitinib and in none who received placebo; as compared with placebo, tofacitinib was associated with increased lipid levels. The authors concluded that in patients with moderately to severely active ulcerative colitis, tofacitinib was more effective as induction and maintenance therapy than placebo. (Funded by Pfizer; OCTAVE Induction 1, OCTAVE Induction 2, and OCTAVE Sustain ClinicalTrials.gov numbers, NCT01465763 , NCT01458951 , and NCT01458574 , respectively.).

In the Open-label Extension Study (Study UC-IV), 914 patients were treated of which 156 received 5 mg twice daily and 758 received 10 mg twice daily. Of the 905 patients who were assigned to tofacitinib 10 mg twice daily in the 8-week induction studies (Study UC-I or Study UC-II), 322 patients completed the induction studies but did not achieve clinical response. Of these 322 patients, 291 continued to receive tofacitinib 10 mg twice daily (unblinded) and had available data after an additional 8 weeks in Study UC-IV. After 8 additional weeks (a total of 16 weeks treatment), 149 patients achieved clinical response, and 25 patients achieved remission (based on central endoscopy read). Among those 144 patients who achieved clinical response by 16 weeks and had available data at Week 52, 65 patients achieved remission (based on local endoscopy read) after continued treatment with tofacitinib 10 mg twice daily for 52 weeks.

Panés et al (2018) evaluated health-related quality of life [HRQoL] in tofacitinib UC Phase 3 studies. Patients ≥ 18 years old in OCTAVE Induction 1 [N = 598] and 2 [N = 541] with moderately to severely active UC were randomised [1:4] to placebo or tofacitinib 10 mg twice daily [BID] for 8 weeks. Subsequently, OCTAVE Sustain re-randomised [1:1:1] clinical responders [N = 593] from induction studies to placebo, tofacitinib 5 mg BID, or 10 mg BID, for 52 weeks. Inflammatory Bowel Disease Questionnaire [IBDQ] and SF-36v2® Health Survey [SF-36v2] assessed HRQoL. In OCTAVE Induction 1 and 2, mean changes from baseline IBDQ were greater with tofacitinib 10 mg BID at Week 8 [28.9 and 31.5] versus placebo [15.4 and 17.2; p < 0.0001]; mean changes from baseline SF-36v2 Physical and Mental Component Summaries [PCS/MCS] were also greater with 10 mg BID [PCS: 6.8 and 6.8; MCS: 6.8 and 7.6] versus placebo [PCS: 2.5 and 4.6; MCS: 3.5 and 4.4; p < 0.01]. In OCTAVE Sustain atWeek 52, changes in IBDQ were maintained with tofacitinib 5 mg [-1.3] and 10 mg BID [0.6], and larger with placebo [-20.2; p < 0.0001]. Changes in SF-36v2 PCS/MCS were also maintained with 5 mg [PCS: 0.0; MCS: -1.0] and 10 mg BID [PCS: 0.3; MCS: 0.1] versus placebo [PCS: -5.2; MCS: -6.7; p < 0.0001] at Week 52 in OCTAVE Sustain. The authors concluded tofacitinib 10 mg BID induction therapy significantly improved HRQoL versus placebo at Week 8. Improvements were maintained through 52 weeks' maintenance therapy with tofacitinib 5 mg and 10 mg BID.

Perrier and Rutgeerts (2012) stated that several anti-tumor necrosis factor-alpha agents are currently used to treat Crohn's disease and ulcerative colitis.  Although these agents have markedly improved the treatment of inflammatory bowel diseases, up to 50 % of the patients have no sustained benefit due to non-response, loss of response or intolerance.  Novel therapies targeting other immune pathways are under study, such as antibodies targeting the IL-12/IL-23 pathway, and have shown interesting preliminary results.  In parallel, anti-adhesion therapies limiting the recruitment of cells to the gut will reach the clinic in the coming years.  Small molecules inhibiting the production of pro-inflammatory cytokines are already used in the clinic for RA, and tofacitinib appears to have great potential to treat ulcerative colitis.

Investigational Use

Tofacitinib is also being investigated in the treatment of dry eye disease, and plaque psoriasis as well as prevention of organ transplant rejection. However, its effectiveness for these diseases/conditions has not been established.

Dry Eye Disease

In a phase I/II prospective, randomized, vehicle- and comparator-controlled clinical trial, Huang et al (2012) evaluated the immuno-modulatory effect of topical ophthalmic tofacitinib after an 8-week treatment period in patients with dry eye disease (DED).  A total of 82 patients with moderate-to-severe DED enrolled in this study.  Patients received 1 of 5 doses of tofacitinib (0.0003 %, 0.001 %, 0.003 %, or 0.005 % twice-daily [BID] or 0.005 % once-daily [QD]), active comparator (cyclosporine ophthalmic emulsion, 0.05 % [Restasis]), or vehicle control BID for 8 weeks.  Conjunctival impression cytology and tear fluid samples were collected at baseline and after an 8-week treatment period.  Conjunctival cells were analyzed by flow cytometry for human leukocyte antigen DR-1 (HLA-DR).  Tear fluids were analyzed by microsphere-based immunoassays for tear levels of cytokines and inflammation markers.  Main outcome measures were reduction in inflammation assessed by change from baseline in conjunctival cell surface level of HLA-DR and tear level of cytokines and inflammation markers.  At week 8, a decrease in conjunctival cell surface expression of HLA-DR was observed in patients treated with tofacitinib 0.005 % QD and 0.003 % BID: 71 % and 67 % of baseline, respectively, compared with 133 % of baseline in patients treated with vehicle (p = 0.023 and p = 0.006, compared with vehicle, respectively).  Matrix metallo-proteinase (MMP)-3 in tears was reduced from baseline at week 8 (40 % of baseline, p = 0.035) in the tofacitinib 0.005 % QD group, whereas the vehicle group showed 77 % of baseline (p > 0.20).  Interleukin (IL)-1β in tears was 36 % of baseline (p = 0.053) in the tofacitinib 0.005 % QD group and 95 % of baseline (p > 0.20) in the vehicle group.  Several other cytokines and inflammation markers in tears, including MMP-9, IL-15, IL-17A, and IL-12p70, were markedly reduced in the tofacitinib 0.005 % QD group but not the vehicle group.  There was an association between the changes in HLA-DR and the tear inflammation markers (p < 0.05): HLA-DR with IL-12p70 (r = 0.49) and IL-1β (r = 0.46), IL-12p70 with IL-1β (r = 0.90), and IL-17A with MMP-9 (r = 0.82).  The authors concluded that topical ophthalmic tofacitinib may act as an immuno-modulator in patients with DED.  Treatment for 8 weeks showed a promising reduction of conjunctival cell surface HLA-DR expression and tear levels of pro-inflammatory cytokines and inflammation markers.  These preliminary findings need to be validated by well-designed studies.

Organ Transplant

Wojciechowski and Vincenti (2011) discussed the mechanism of action and important clinical trial data in renal transplantation for tofacitinib, formerly known as CP-690,550 and tasocitinib.  JAKs are cytoplasmic tyrosine kinases that participate in the signaling of a broad range of cell surface receptors, especially members of the cytokine receptor common gamma chain family.  JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated efficacy in autoimmune disorders such as RA.  Non-human primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared with vehicle control.  Renal transplant clinical trials in humans have demonstrated tofacitinib to be non-inferior to cyclosporine in terms of rejection rates and graft survival.  There was also a lower rate of new-onset diabetes after transplant.  However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis.  The authors concluded that tofacitinib may be a promising alternative to calcineurin inhibitors.  Moreover, the optimal therapeutic window is still being determined.

Wojciechowski and Vincenti (2013) discussed the mechanism of action and important kidney transplant clinical trial data for tofacitinib.  Current maintenance immunosuppressive protocols that rely on calcineurin inhibitors have long-term nephrotoxicity and negative impact on cardio-metabolic risk factors.  JAK3 inhibition has immunosuppressive effects and treatment with tofacitinib in clinical trials has demonstrated effectiveness in autoimmune disorders such as RA.  Non-human primate models of renal transplantation demonstrated prolonged graft survival with tofacitinib compared to control.  Renal transplant clinical trials in humans have demonstrated tofacitinib to be non-inferior to cyclosporine in terms of rejection rates and graft survival.  There was also a lower rate of new onset diabetes after transplant.  However, there was a trend toward more infections, including cytomegalovirus and BK virus nephritis.  The authors concluded that tofacitinib may be a promising alternative to calcineurin inhibitors; and the optimal therapeutic window is still being determined.

Alopecia Universalis

An UpToDate review on “Management of alopecia areata” (Messenger, 2014) states that “Regrowth of hair in a patient with longstanding alopecia universalis during treatment with tofacitinib (a small molecule selective Janus kinase 1/3 inhibitor) for psoriasis has been documented in a case report.  After eight months of tofacitinib treatment, the patient had full regrowth of hair at all body sites.  A beneficial effect of tofacitinib on alopecia areata may result from inhibition of T lymphocyte activation.  Further study is necessary to confirm the efficacy of this treatment.  Tofacitinib therapy is associated with increased risk for infection, including serious infections.  The development of malignancy and laboratory abnormalities has also been reported in patients receiving tofacitinib therapy for other diseases”.

Gupta et al (2016) stated that autoimmune-triggered non-scarring hair loss is a feature of alopecia areata (AA).  Initially patchy and often self-limited, severe hair loss forms include the complete loss of scalp hair or alopecia totalis (AT) and complete loss of all hair or alopecia universalis (AU).  For AT and AU a reliable treatment has remained elusive.  The targeted kinase inhibitor tofacitinib, in current use for treatment of other immune diseases, has been hypothesized as a viable option for AA, AT and AU therapy and a few case reports supported this.  These researchers provided evidence for the effectiveness of tofacitinib in the treatment of AU.  Two patients diagnosed with long-term AU were prescribed tofacitinib citrate at a dosage of 5 mg twice-daily and observed for 8 months.  In the 1st patient, beard growth was significant by 3 months of treatment.  By 6 months of treatment, hair growth was apparent throughout the entire body.  By 8 months of treatment, scalp hair continued to grow longer and thicker.  In addition, eyelashes and eyebrows were established.  In the 2nd patient, a noticeable increase in scalp hair was present just 1 month into treatment.  By 4 months into treatment, significant scalp re-growth was observed as well as eyelash, eyebrow and beard regrowth.  Axillary hair regrowth and isolated leg hair was noted by 8 months.  The authors concluded that in their patients, tofacitinib successfully alleviated AU in the absence of significant adverse side-effects.  They recommended that further study be required to establish safety and confirm efficacy.

Furthermore, an UpToDate review on “Management of alopecia areata” (Messenger, 2017) states that “Janus kinase inhibitors -- Regrowth of hair in a patient with longstanding alopecia universalis during treatment with tofacitinib (a small molecule selective Janus kinase 1/3 inhibitor) for psoriasis has been documented in a case report.  After 8 months of tofacitinib treatment (5 mg twice-daily for 2 months followed by 10 mg in the morning and 5 mg at night thereafter), the patient had full regrowth of hair at all body sites.  Remission of alopecia areata-associated nail dystrophy (e.g., brittle nails, thin nails, longitudinal ridging, onycholysis, pitting) in 3 patients during treatment with tofacitinib (10 to 15 mg per day in 2 divided doses) for alopecia universalis has also been reported.  Nail improvement occurred over a period of 5 to 6 months.  A beneficial effect of tofacitinib on alopecia areata may result from inhibition of T lymphocyte activation.  Further study is necessary to confirm the efficacy of this treatment.  Tofacitinib therapy is associated with increased risk for infection, including serious infections.  The development of malignancy and laboratory abnormalities has also been reported in patients receiving tofacitinib therapy for other diseases.  Further support for a potential role for Janus kinase inhibitors in the treatment of alopecia areata stems from case reports describing the use of oral ruxolitinib (a Janus kinase 1/2 inhibitor approved by the US Food and Drug Administration for the treatment of myelofibrosis).  In one report, all 3 patients with moderate to severe alopecia areata experienced near-complete regrowth of hair within 3 to 5 months during treatment with oral ruxolitinib (20 mg twice-daily).  In addition, topical formulations of ruxolitinib and tofacitinib have yielded promising results in mouse models of alopecia areata.  In a patient with refractory alopecia universalis, treatment with ruxolitinib 0.6 % cream (twice-daily for 12 weeks) appeared to stimulate almost full eyebrow regrowth and approximately 10 % regrowth of scalp hair.  Of note, a small, stable decrease in the patient’s white blood cell count occurred during treatment.  Additional study is necessary prior to conclusions about the efficacy and safety of topical Janus kinase inhibitors for alopecia areata.  Topical formulations of ruxolitinib and tofacitinib are not commercially available”.

Plaque Psoriasis

Papp et al (2012) noted that tofacitinib is a novel, oral janus kinase inhibitor under investigation as a potential treatment for plaque psoriasis.  In a phase IIb, 12-week, dose-ranging study, these researchers characterized the exposure-response, safety and effectiveness of tofacitinib versus placebo in patients with moderate-to-severe chronic plaque psoriasis.  A total of 197 patients were randomized.  The primary end point was the proportion of patients achieving a greater than or equal to 75 % reduction in the Psoriasis Area and Severity Index (PASI 75) score at week 12.  At week 12, PASI 75 response rates were significantly higher for all tofacitinib twice-daily groups: 25.0 % (2 mg; p < 0.001), 40.8 % (5 mg; p < 0.0001) and 66.7 % (15 mg; p < 0.0001), compared with placebo (2.0 %).  Significant increases in the proportion of PASI 75 responses were observed by week 4 and were maintained at week 12.  Exposure-response over the 0 to 15 mg tofacitinib twice-daily dose range was successfully characterized.  PASI 50, PASI 90 and Physician's Global Assessment response rates were also higher for tofacitinib versus placebo.  The most frequently reported AEs were infections and infestations: 22.4 % (2 mg twice-daily), 20.4 % (5 mg twice-daily), 36.7 % (15 mg twice-daily) and 32.0% (placebo).  Discontinuations due to AEs were 6.0 %, 2.0 %, 4.1 % and 6.1 % of patients in the placebo, 2, 5 and 15 mg twice-daily tofacitinib groups, respectively.  Dose-dependent increases from baseline in mean serum high-density lipoprotein, low-density lipoprotein and total cholesterol, and decreases in hemoglobin and neutrophils were observed.  The authors concluded that the short-term treatment with oral tofacitinib results in significant clinical improvement in patients with moderate-to-severe plaque psoriasis and is generally well-tolerated.  These promising findings need to be validated in prospective, randomized, controlled trials with longer follow-up periods.

In a phase IIa clinical trial, Ports et al (2013) evaluated the safety, effectiveness, local tolerability and systemic pharmacokinetics of topical tofacitinib in mild-to-moderate plaque psoriasis.  Two tofacitinib ointment formulations were evaluated in this multi-center, double-blind, vehicle-controlled trial.  A total of 71 patients were randomized 2 : 1 : 2 : 1 to 2 % tofacitinib ointment 1, vehicle 1, 2 % tofacitinib ointment 2 and vehicle 2, each administered twice-daily for 4 weeks to a single fixed 300 cm(2) treatment area containing a target plaque with or without 1 or more non-target plaques and normal skin.  The primary end-point of percentage change from baseline in the Target Plaque Severity Score at week 4 demonstrated statistically significant improvement for ointment 1 [least squares mean (LSM) -54.4 %] versus vehicle 1 (LSM -41.5 %), but not ointment 2 (LSM -24.2 %) versus vehicle 2 (LSM -17.2 %).  Secondary end-points (target plaque area and Itch Severity Item) improved similarly for tofacitinib ointment versus corresponding vehicle.  Adverse event occurrence was similar across treatment groups.  All AEs were mild or moderate and none was serious or led to subject discontinuation.  One application-site AE (erythema) was reported.  Tofacitinib mean systemic exposure was minimal and was greater for ointment 1 than for ointment 2.  The authors concluded that tofacitinib ointment 1 was well-tolerated and effective compared with vehicle for the treatment of plaque psoriasis.  Moreover, they stated that further study of topical tofacitinib for psoriasis treatment is warranted.

Wu and colleagues (2016) noted that tofacitinib is being investigated as a treatment for psoriasis.  These researchers evaluated the effects of tofacitinib on cardiovascular (CV) risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis.  Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib.  Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged.  There were no changes in blood pressure and glycated hemoglobin levels; CRP levels decreased.  The IRs of a MACE were low and similar for both tofacitinib doses.  Among 3,623 subjects treated with tofacitinib, the total patient-years of exposure was 5,204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95 % confidence interval [CI]: 0.22 to 0.57) patients with events per 100 patient-years.  The authors concluded that while treatment with tofacitinib was associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio did not change; there were no unfavorable changes in several CV risk factors, and the incidence of MACEs was low.  The major drawback of this study was that there was relatively short follow-up time for patients who had MACEs.

Ankylosing Spondylitis

Ungprasert and colleagues (2017) stated that patients with ankylosing spondylitis (AS) often do not have a satisfactory response to, or could not tolerate, non-steroidal anti-inflammatory drugs (NSAIDs).  Several biologic agents are available for such patients.  However, the comparative efficacy of these treatments remains unknown as head-to-head randomized controlled trials (RCTs) are not available.  In a systematic review and meta-analysis, RCTs examining the efficacy of biologic agents in patients with AS who had inadequate response to, or could not tolerate, NSAIDs were identified.  If at least 2 RCTs were available for a given biologic agent, the pooled odds ratio (OR) and 95 % confidence interval (CI) of achieving 20 % improvement according to the Ankylosing Spondylitis Assessment Study group response criteria 20 (ASAS20) across trials were calculated.  The pooled OR for each biologic agent was then compared to each other using the indirect comparison technique.  A total of 14 RCTs of older TNF inhibitors, 2 RCTs of secukinumab, 1 RCT of certolizumab, and 1 RCT of tofacitinib were identified.  No significant difference in any indirect comparisons was observed with the p values ranging from 0.12 to 0.74.  The likelihood of achieving the ASAS20 response in patients AS who failed or could not tolerate NSAIDs was not significantly different between older TNF inhibitors, secukinumab, certolizumab, and tofacitinib.  However, the analysis is limited by the small sample size with only one RCT for certolizumab and tofacitinib.

Furthermore, an UpToDate review on “Assessment and treatment of ankylosing spondylitis in adults” (Yu, 2017) does not mention tofacitinib as a therapeutic option.

Atopic Dermatitis

Levy and associates (2015) evaluated the effectiveness of tofacitinib in the treatment of moderate-to-severe atopic dermatitis (AD).  A total of 6 consecutive patients with moderate-to-severe AD who had failed standard treatment were treated with tofacitinib citrate.  Response to treatment was assessed using the Scoring of AD index.  Decreased body surface area (BSA) involvement of dermatitis and decreased erythema, edema/papulation, lichenification, and excoriation were observed in all patients.  The Scoring of AD index decreased by 66.6 % from 36.5 to 12.2 (p < 0.05) during 8 to 29 weeks of treatment.  There were no AEs.  The authors concluded that tofacitinib citrate may be beneficial in the treatment of moderate-to-severe AD.  The major drawbacks of this study were its small sample size, lack of a placebo control group, and the possibility of bias.

In a 4-week, phase IIa, randomized, double-blind, vehicle-controlled clinical trial, Bissonnette and colleagues (2016) investigated the use of tofacitinib for the topical treatment of AD.  A total of 69 adults with mild-to-moderate AD were randomized 1:1 to 2 % tofacitinib or vehicle ointment twice-daily.  Percent change from baseline (CFB) in Eczema Area and Severity Index (EASI) score at week 4 was the primary end-point.  Secondary efficacy end-points included: percent CFB in Body Surface Area (BSA), CFB in EASI Clinical Signs Severity Sum Score, proportion of patients with Physician's Global Assessment (PGA) response; and CFB in patient-reported pruritus.  Safety, local tolerability and pharmacokinetics were monitored.  Mean percent CFB at week 4 in EASI score was significantly greater (p < 0.001) for tofacitinib (-81.7 %) versus vehicle (-29.9 %).  Tofacitinib-treated patients showed significant (p < 0.001) improvements versus vehicle across all pre-specified efficacy end-points and pruritus at week 4.  Significant improvements in EASI, PGA and BSA were observed by week 1 and pruritus by day 2.  Safety/local tolerability were generally similar between treatments, although more AEs were observed for vehicle versus tofacitinib.  The authors concluded that tofacitinib ointment showed significantly greater efficacy versus vehicle across end-points, with early onset of effect, and comparable safety/local tolerability to vehicle.  They stated that JAK inhibition through topical delivery is potentially a promising therapeutic target for AD.

Also, an UpToDate review on “Treatment of atopic dermatitis (eczema)” (Westin and Howe, 2017) states that “Although topical tofacitinib seems a promising treatment for atopic dermatitis, larger studies of longer duration including patients with more severe disease are needed to evaluate its long-term efficacy and safety”.

Autoimmune Lymphoproliferative Syndrome and Lymphadenopathy

Yokoyama and co-workers (2015) noted that autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant genetic disorder of lymphocyte homeostasis with defective Fas-mediated apoptosis.  Current therapies for ALPS primarily target autoimmune manifestations with non-specific immune suppressants with variable success thus highlighting the need for better therapeutics for this disorder.  The spectrum of clinical manifestations of ALPS is mirrored by MRL/lpr mice that carry a loss of function mutation in the Fas gene and have proven to be a valuable model in predicting the effectiveness of several therapeutics that are front-line modalities for the treatment of ALPS.  These researchers evaluated the potential effectiveness of tofacitinib as a single-agent modality against ALPS using MRL/lpr mice.  These investigators demonstrated that a 42-day course of tofacitinib therapy led to a lasting reversal of lymphadenopathy and autoimmune manifestations in the treated MRL/lpr mice.  Specifically, in treated mice the peripheral blood white blood cell counts were reversed to near normal levels with almost a 50 % reduction in the TCRαβ(+)CD4(-)CD8(-)T lymphocyte numbers that coincided with a parallel increase in CD8(+) T cells without a demonstrable effect on CD4(+) lymphocytes including FoxP3(+) regulatory T cells.  The elevated plasma IgG and IgA levels were also drastically lowered along with a significant reduction in plasmablasts and plasmacytes in the spleen.  The authors concluded that on the basis of these results, it is likely that tofacitinib would prove to be a potent single-agent therapeutic modality capable of ameliorating both offending lymphadenopathy as well as autoimmunity in ALPS patients.

Also, an UpToDate review on “Autoimmune lymphoproliferative syndrome (ALPS): Management and prognosis.” (Bleesing, 2017) does not mention tofacitinib as a therapeutic option.

Corneal Inflammation

Sakimoto and Ishimori (2016) evaluated an anti-inflammatory effect of topical administration of tofacitinib on corneal inflammation.  Topical instillation of either tofacitinib or phosphate-buffered saline (PBS) was applied after wounding BALB/c mice corneas with alkali burn.  Topical instillation was performed until day 14 after injury and injured eye was analyzed.  The vascularized area in the alkali burned cornea was significantly reduced in the tofacitinib group compared with that in the PBS group.  The immune-reactivity of Gr-1, F4/80, interferon-gamma (IFN-γ), and phosphorylated STAT(signal transducer and activator of transcription)1 in corneal stroma was diminished significantly in the tofacitinib group.  Using laser capture micro-dissection system and quantitative polymerase chain reaction (PCR) array analysis, the expression levels of CXCL9, CXCL5, CCL7, CCL2, MMP (matrix metalloproteinase)-9, and STAT1 in corneal stroma were down-regulated in the tofacitinib group.  In in-vitro study, human fibroblast pretreated by IFN-γ showed phosphorylation of STAT1, and this phosphorylation was down-regulated by adding tofacitinib to the culture medium.  The authors concluded that topical application of JAK inhibitor resulted in down-regulation of JAK- or IFN-γ-related molecules.  Thus, they deduced that application of JAK inhibitor for topical instillation may contribute to the treatment of corneal inflammation.

Juvenile Idiopathic Arthritis

Hugle and Horneff (2016) stated that juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in childhood.  Synthetic DMARDs have been used in its treatment since the 1980s and have led to substantial improvement of quality of life and disease outcome.  Recent pharmacological research has focused on newer medications, especially biologic agents.  Synthetic DMARDS, especially MTX, rightfully remain the 1st-line treatment of most categories of juvenile arthritis, as attested by several international guidelines.  A substantial body of evidence supports these medications, and recent research tries to clarify their optimal use in the clinical setting, both as monotherapy and in combination with biologics.  In addition, new forms of synthetic DMARDs are in the research pipeline, or are already used for RA.  The authors stated that MTX remains the preferred 1st-line medication for poly-articular arthritis, with leflunomide as a viable alternative in case of intolerance or toxicity, despite lack of approval in Europe and the United States.  Sulfasalazine and hydroxychloroquine are used only rarely in clinical practice, considered in combination with MTX if biologics are not available.  New synthetic DMARDS are in the research pipeline for JIA, in the form of small molecules.  Tofacitinib was one of the key words mentioned in this study.

Also, an UpToDate review on “Systemic juvenile idiopathic arthritis: Treatment” (Kimura, 2017) does not mention tofacitinib as a therapeutic option.

Mast Cell Activation Syndrome

Afrin and colleagues (2017) stated that mast cell activation syndrome (MCAS) is a collection of illnesses of inappropriate MC activation with little to no neoplastic MC proliferation, distinguishing it from mastocytosis.  MCAS presents as chronic, generally inflammatory multisystem poly-morbidity likely driven in most by heterogeneous patterns of constitutively activating mutations in MC regulatory elements, posing challenges for identifying optimal mutation-targeted treatment in individual patients.  Targeting commonly affected downstream effectors may yield clinical benefit independent of up-stream mutational profile.  For example, both activated KIT and numerous cytokine receptors activate the JAKs.  Thus, JAK-inhibiting therapies may be useful against the down-stream inflammatory effects of MCAS.  The oral JAK1/JAK3 inhibitor, tofacitinib, is currently approved for RA and is in clinical trials for other chronic inflammatory disorders.  The authors reported 2 patients with MCAS who rapidly gained substantial symptomatic response to tofacitinib; their improvement suggested the need for further evaluation of this class of drugs in MCAS treatment.

Spondyloarthritis

Braun and colleagues (2015) stated that his review of new therapies in axial and peripheral spondyloarthritis (SpA) comprising psoriatic arthritis (PsA) showed that, in addition to the established anti-TNF agents infliximab, etanercept, adalimumab, golimumab, certolizumab and the first bio-similar approved in the EU, there are at least 2 emerging biologics in the field of SpA: ustekinumab, a compound targeting IL12/IL-23 via the p40 subunit of both cytokines works for psoriasis and PsA and probably also for Crohn's disease, and the anti-IL-17 antibody secukinumab that has also been shown to work in psoriasis, both compounds appeared also work in ankylosing spondylitis.  In addition, the potential of 2 small molecules, apremilast a phoshodiesterase4 inhibitor and tofacitinib, a JAK inhibitor was also discussed.  The authors concluded that since, in contrast to RA, the therapeutic array in SpA is currently limited to TNF-blockers, and since there is still an unmet need because some patients did not respond to anti-TNF therapy at all or they lost response, new agents with a different mechanism of action are needed.

Also, UpToDate reviews on “Assessment and treatment of ankylosing spondylitis in adults” (Yu, 2017) and “Treatment of peripheral spondyloarthritis” (Yu and van Tubergen, 2017) do not mention tofacitinib as a therapeutic option.

Systemic Lupus Erythematosus

Furumoto and associates (2017) noted that dysregulation of innate and adaptive immune responses contributes to the pathogenesis of systemic lupus erythematosus (SLE) and its associated pre-mature vascular damage.  To-date, no drug targets both systemic inflammatory disease and the cardiovascular complications of SLE.  Tofacitinib is a JAK inhibitor that blocks signaling down-stream of multiple cytokines implicated in lupus pathogenesis.  While clinical trials have shown that tofacitinib exhibits significant clinical effectiveness in various autoimmune diseases, its role in SLE and the associated vascular pathology remains to be characterized.  In this study, MRL/lpr lupus-prone mice received tofacitinib or vehicle by gavage for 6 weeks (therapeutic arm) or 8 weeks (preventive arm).  Nephritis, skin inflammation, serum autoantibody levels and cytokines, mononuclear cell phenotype and gene expression, neutrophil extracellular traps (NETs) release, endothelium-dependent vaso-relaxation, and endothelial differentiation were compared in treated and untreated mice.  Treatment with tofacitinib led to significant improvement in measures of disease activity including nephritis, skin inflammation, and autoantibody production.  In addition, tofacitinib treatment reduced serum levels of pro-inflammatory cytokines and interferon responses in splenocytes and kidney tissue.  Tofacitinib also modulated NETs formation and significantly increased endothelium-dependent vaso-relaxation and endothelial differentiation.  The drug was effective as both preventive and therapeutic strategies.  The authors concluded that tofacitinib modulated the innate and adaptive immune responses, ameliorated murine lupus and improves vascular function.  They stated that these results indicated that JAK inhibitors have the potential to be beneficial in SLE and its associated vascular damage.

Vitiligo

Craiglow and King (2015) noted that vitiligo is a common condition that is often emotionally devastating for patients.  At present, no reliably effective treatments are available.  Recent advances in the understanding of the pathogenesis of vitiligo suggested that JAK inhibitors may be a therapeutic option.  These investigators reported a case of generalized vitiligo for which treatment with tofacitinib citrate resulted in significant re-pigmentation.  The authors concluded that the results of this case-study suggested that tofacitinib and other JAK inhibitors may be effective in the treatment of vitiligo.  They stated that additional studies are needed to confirm their safety and effectiveness.

Kostovic and colleagues (2017) presented updated data summary on the tofacitinib in the field of dermatology.  These investigators undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria.  Technical reports on tofacitinib from the FDA and European Medical Agency (EMA) were also included.  A total of 43 papers were included in this review.  These researchers reported current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata.  The authors concluded that JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo.  However, despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies are needed to determine the adequate risk-to-benefit ratio.

Also, an UpToDate review on “Vitiligo: Management and prognosis” (Grimes, 2017) does not mention tofacitinib as a therapeutic option.

Appendix

Recommended Dosage:

• Rheumatoid Arthritis: XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. Decrease dose to 5 mg once daily in patients with moderate and severe renal impairment or moderate hepatic impairment.
• Psoriatic Arthritis (in combination with nonbiologic DMARDs): XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily. Decrease dose to 5 mg once daily in patients with moderate and severe renal impairment or moderate hepatic impairment
• Ulcerative Colitis: XELJANZ 10 mg twice daily for at least 8 weeks; then 5 or 10 mg twice daily. Discontinue after 16 weeks of 10 mg twice daily, if adequate therapeutic benefit is not achieved. Half the total daily dosage is recommended for patients with moderate and severe renal impairment or moderate hepatic impairment:

Table: Brands of Targeted Immune Modulators and FDA-approved Indications:

Brand Name	Generic Name	FDA Labeled Indications
Actemra	tocilizumab	Giant cell arteritis Juvenile idiopathic arthritis Rheumatoid arthritis Systemic juvenile idiopathic arthritis Cytokine release syndrome (CRS)
Cimzia	certolizumab	Ankylosing spondylitis Crohn's disease Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis
Cosentyx	secukinumab	Ankylosing spondylitis Plaque psoriasis Psoriatic arthritis
Enbrel	etanercept	Ankylosing spondylitis Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthrits Rheumatoid arthritis
Entyvio	vedolizumab	Crohn's disease Ulcerative colitis
Humira	adalimumab	Ankylosing spondylitis Crohn's disease Hidradenitis suppurativa Juvenile idiopathic arthritis Plaque psoriasis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis Uveitis
Ilaris	canakinumab	Periodic fever syndromes   Systemic juvenile idiopathic arthritis
Ilumya	tildrakizumab-asmn	Plaque psoriasis
Inflectra	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Kevzara	sarilumab	Rheumatoid arthritis
Kineret	anakinra	Cryopyrin-associated periodic syndromes Rheumatoid arthritis
Olumiant	baricitinib	Rheumatoid arthritis
Orencia	abatacept	Juvenile idiopathic arthritis Psoriatic arthritis Rheumatoid arthritis
Otezla	apremilast	Plaque psoriasis Psoriatic arthritis
Remicade	infliximab	Ankylosing spondylitis Crohn's disease Psoriatic arthritis Plaque psoriasis Rheumatoid arthritis Ulcerative colitis
Rituxan	rituximab	Granulomatosis with polyangiitis Microscopic polyangiitis Pemphigus vulgaris Rheumatoid arthritis
Siliq	brodalumab	Plaque psoriasis
Simponi	golimumab	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis Ulcerative colitis
Simponi Aria	golimumab intravenous	Ankylosing spondylitis Psoriatic arthritis Rheumatoid arthritis
Stelara	ustekinumab	Crohn's disease Plaque psoriasis Psoriatic arthritis
Taltz	ixekinumab	Plaque psoriasis Psoriatic arthritis
Tremfya	guselkumab	Plaque psoriasis
Tysabri	natalizumab	Crohn's disease Multiple sclerosis
Xeljanz	tofacitinib	Rheumatoid arthritis Psoriatic arthritis Ulcerative Colitis
Xeljanz XR	tofacitinib, extended release	Rheumatoid arthritis Psoriatic arthritis Ulcerative colitis

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":
XELJANZ (tofacitinib):
No specific code
Other CPT codes related to the CPB:
71045 - 71048	Radiologic examination, chest
86480	Tuberculosis test, cell mediated immunity antigen response measurement; gamma interferon
86481	Tuberculosis test, cell mediated immunity antigen response measurement; enumeration of gamma interferon – producing T cells in cell suspension
86580	Skin test; tuberculosis, intradermal
Other HCPCS codes related to the CPB:
J9250	Methotrexate sodium, 5 mg
J9260	Methotrexate sodium, 50 mg
ICD-10 codes covered if selection criteria are met:
K51.00 - K51.919	Ulcerative colitis [Xeljanz IR Formulation only, not XR]
M05.00 - M05.9	Rheumatoid arthritis with rheumatoid factor [moderately to severely active in adults who have had an inadequate response to, or who are intolerant of, methotrexate]
M06.00 - M06.9	Other rheumatoid arthritis [moderately to severely active in adults who have had an inadequate response to, or who are intolerant of, methotrexate]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
D89.40 - D89.49	Mast cell activation syndrome and related disorders
D89.82	Autoimmune lymphoproliferative syndrome [ALPS]
H02.731 - H02.739	Vitiligo of eyelid and periocular area
H16.201 - H16.299	Keratoconjunctivitis
H16.9	Unspecified keratitis
K50.00 - K50.919	Crohn's disease [regional enteritis]
L20.80-L20.9	Other and unspecified atopic dermatitis
L40.0 - L40.9	Psoriasis
L40.50 - L40.59	Arthropathic psoriasis
L63.0 - L66.9	Alopecia
L80	Vitiligo
M08.00 - M08.09	Unspecified juvenile rheumatoid arthritis [idiopathic]
M32.10 - M32.19	Systemic lupus erythematosus with organ or system involvement
M35.0 - M35.09	Sicca syndrome [Sjögren]
M45.0 - M45.9	Ankylosing spondylitis.
M47.011 - M47.896	Spondylosis
R59.1	Generalized enlarged lymph nodes
T86.00 - T86.99	Complications of transplanted organs and tissue
Z94.0 - Z94.9	Transplanted organ and tissue status

The above policy is based on the following references: