Drugs that act on the immune system: Immunosuppressive and immunostimulatory drugs

C H A P T E R

36 Drugs that act on the immune system: Immunosuppressive and immunostimulatory drugs Cucnhat Walker, PharmD, BCPS, MPH*, Sidhartha D. Ray, PhD, FACN†,1 *Department of Clinical and Administrative Sciences, Larkin University College of Pharmacy, Miami, FL, United States † Department of Pharmaceutical & Biomedical Sciences, Touro College of Pharmacy & School of Osteopathic Medicine, Manhattan, NY, United States 1 Corresponding author: [email protected]

Abbreviations 6-TGN ABMR ADR aTCMR bDMARDs cGVHD CI CMV CNIs CsA CVD DM DMF dnDSA EBV FDA GA HBV IFN-β Ig IV MMF MPA MPS NUDT15 R139C PML RA RRMS

6-thioguanosine triphosphate acute antibody-mediated rejection adverse drug reaction acute T-cell-mediated rejection biological disease-modifying antirheumatic drugs chronic graft-vs-host disease calcineurin inhibitor cytomegalovirus calcineurin inhibitors cyclosporine cardiovascular disease diabetes mellitus dimethyl fumarate de novo donor-specific antibodies Epstein–Barr virus Food & Drug Administration glatiramer acetate hepatitis B virus interferon-β immunoglobulin intravenous mycophenolate mofetil mycophenolic acid mycophenolate sodium nucleoside diphosphate-linked moiety X-type motif 15 encoding p.Arg139CysMS multiple sclerosis progressive multifocal leukoencephalopathy rheumatoid arthritis relapsing–remitting MS

Side Effects of Drugs Annual, Volume 41 ISSN: 0378-6080 https://doi.org/10.1016/bs.seda.2019.07.008

SQ TNFi TPMP

subcutaneous tumor necrosis factor inhibitors thiopurine methyltransferase

INTRODUCTION Decades of research have suggested that immunomodulation is a complex area in medicine. Therapeutic interventions are aimed at modifying the immune response which is often faced with more disastrous consequences because it is challenging to target specific component of the immune system. Manipulation of the immune system often augments established infection in immunodeficient individuals; therefore, treatment of the underlying cause often bears paramount importance. It is fairly established that immune defects can seldom be corrected; therefore, launching of a new immune system by allogeneic stem cell transplantation often presents a viable option. Immune modulation by immunosuppressive and/or immunostimulating agents is frequently faced with unexpected side effects, adverse reactions, toxicities, diverse forms of allergies, hypersensitivity reactions and/or the development of resistance. In the arena of immunotherapeutics, organ transplantation via immune modulation remains the most challenging. This review presents analyses of important case studies on the side effects, adverse

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© 2019 Elsevier B.V. All rights reserved.

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reactions, and toxicities that are associated with the use of immunosuppressive and immunostimulating agents in clinical settings.

IMMUNOSUPPRESSIVE DRUGS Abatacept Abatacept (Orencia®) is a selective immunosuppressant, which binds to CD80 and CD86 on antigenpresenting cells to inhibit the required interaction of CD28 on antigen-presenting T cells for cellular activation [1S]. It was approved by the Food & Drug Administration (FDA) in 2005 for moderately to severely active rheumatoid arthritis (RA) in adults and moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients aged 6 years and older. Administration A retrospective study reviewed 398 pediatric patients receiving 7585 intravenous (IV) infusions of abatacept, belimumab, cyclophosphamide, immune globulin, infliximab, methylprednisolone, N-acetylcysteine, pamidronate disodium, rituximab, and tocilizumab over the course of 3 years [2C]. Only 31 out of 237 patients who received abatacept IV infusion presented with 5 infusion-related reactions, including 1 episode of rash that was treated with subcutaneous (SQ) epinephrine, 1 throat tightness/ itching/pain, and 3 headaches. Patients with these 5 adverse drug reactions (ADRs) successfully tolerated subsequent infusions. Chronic graft-vs-host disease (cGVHD) A phase I trial was conducted to determine the maximum tolerated dose of abatacept and its safety profile to treat steroid-refractory cGVHD [3C]. 16 adult patients received either 3 or 10 mg/kg given every other week for the first three doses, then monthly for a total of 12 doses. Seven patients had improvement in at least two disease sites based on the 2005 National Institute of Health Consensus Criteria. In addition, there was a 51.3% reduction in prednisone use in clinical responders. Overall, abatacept was well tolerated with no doselimiting toxicities. Dose-limiting toxicities were defined as grade 3 or 4 toxicities judged to be probably or definitively related to abatacept. The observation period for dose-limiting toxicities was from the first dose to 1 month after the sixth dose. There were 3 pulmonary infections which occurred at both dose levels. The authors did not specify dose levels for the other listed adverse events (e.g., 1 incident of rash, 2 fatigue, 1 skin pain, 2 diarrhea, 1 gastritis, and 1 general pain).

Comparative studies A population-based cohort study was conducted using insurance claim database on 84 453 adult patients with confirmed diagnosis of RA and treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) between January 1, 2007 and December 31, 2014 [4C]. This study compared 4328 patients on abatacept to 59 860 patients on other bDMARDs
methotrexate. The use of abatacept was associated with 17% higher rate of cancer overall (adjusted hazard ratio (HR) 1.17, 95% CI 1.06–1.30), especially non-melanoma skin cancer (adjusted hazard ratio 1.20, 95% CI 1.03–1.39). There was no significant difference for other cancer types between the groups. Another population-based cohort study compared the risk of hospitalized infections among adult patients with RA treated with abatacept (n ¼ 13 015) or tumor necrosis factor inhibitors (TNFi) (n ¼ 52 719), using insurance claim database [5C]. Abatacept was associated with a lower rate of hospitalized infections (HR 0.78, 95% CI 0.64–0.95), especially pulmonary infections. Cardiovascular risk A population-based cohort review of 13 036 adult patients with RA treated with either abatacept or TNFi, used insurance claim databases to study cardiovascular risk [6C]. Composite primary cardiovascular disease (CVD) endpoint included myocardial infarction, stroke/transient ischemic attack, or coronary revascularization. Composite secondary CVD endpoint was heart failure and venous thromboembolism. The TNFi investigated were adalimumab, etanercept, certolizumab, golimumab, and infliximab. Abatacept was associated with a 20% reduced composite primary CVD risk compared to TNFi (primary endpoint HR 0.79, 95% CI 0.67–0.92). The overall composite secondary CVD endpoint was not statistically significant. These authors carried out another similar retrospective review for patients with diabetes mellitus (DM) specifically, who were started on abatacept or TNFi in addition to other chronic therapies to treat their RA [7C]. Primary and secondary endpoints were similar to their aforementioned study. In the subgroup analyses, the DM group who were treated with abatacept had a lower composite CVD endpoint than those treated with TNFi (pooled HR 0.74, 95% CI 0.57–0.96). When DM was combined with older age (65 years), statistical significance was not achieved. A retrospective cohort review investigated heart failure rate among 2527 adult patients with RA, treated with either etanercept (n ¼ 1690) or abatacept (n ¼ 837) [8C]. The crude heart failure rate was significantly higher in the abatacept group. After the results were adjusted for age, sex, disease duration, concomitant medications, and comorbidities, there was no significant difference between the two groups.

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Obesity

Opportunistic infections

A systematic review of 24 studies investigated the effect of obesity on clinical responses to bDMARDs in patients with RA, ankylosing spondylitis, axial spondyloarthritis, Crohn’s disease, psoriasis, and psoriatic arthritis [9M]. Studies on patients with RA included TNFi, abatacept, tocilizumab, and rituximab, while studies of the remaining diseases included only TNFi. Therapy duration of the studies on RA and axial spondyloarthritis varied from 4 to 12 months, and those on the remaining disease states varied from 10.5 to 13 months. Dosing regimens were not specified in this analysis. Overall, obesity appeared to affect remission rate and clinical response to TNFi in patients with RA and axial spondyloarthritis. Clinical effects of abatacept, rituximab and tocilizumab were not influenced by obesity.

A 63-year-old Japanese female with a long history of RA was treated with monthly 500-mg IV abatacept and daily 4-mg prednisone for RA exacerbation 15 months prior to her hospital admission [13A]. Four months after her last dose of abatacept, she developed liver injury and became progressively pancytopenic. She was positive for cytomegalovirus (CMV), Epstein–Barr virus (EBV), and aspergillus biomarkers, but negative for hepatitis A, B, C infections and (1,3)-β-D-glucan. Although the EBV DNA level was not obtained immediately prior to abatacept initiation, a high serum EBV load was detected 2 years before her hospital admission, which suggested chronic EBV infection. She died of fulminant liver failure secondary to chronic active infection of the T-cell type. A retrospective chart review assessed the risk for hepatitis B virus (HBV) reactivation on 152 patients with RA, treated with bDMARDs [14C]. These patients had a prior history of resolved HBV infections; 2 out of 29 patients on chronic abatacept therapy had a positive conversion of HBV-DNA level of >20 IU/mL which became negative when treated with entecavir. There was no significant difference in their HBV reactivation rate with each therapy.

Oral lichenoid reaction A 69-year-old Caucasian female with RA treated with abatacept for 3 years presented with painful oral canker sores [10A]. Abatacept dose was not listed. Her daughter was reported to also have the same type of canker sores while being treated with abatacept for an autoimmune disease. She was diagnosed with lichen planus, which resolved after abatacept discontinuation. Medium-vessel vasculitis A 42-year-old male with a 9-year history of psoriasis and psoriatic arthritis was hospitalized with multiple bilateral leg erythematous ulcers 3 months after initiation of abatacept [11A]. Abatacept dosing regimen was not discussed. The lesions were treated with multiple scalpel debridement and different classes of antibiotics. Punch biopsy showed medium-vessel vasculitis. No other trigger was identified besides abatacept initiation. His vasculitis lesions rapidly healed with abatacept withdrawal. Lupus A 66-year-old female who developed interface dermatitis presented as diffuse itching rash on her face, upper chest, and extensor surfaces of both arms, in addition to hair loss and fatigue, after 2 months of abatacept treatment (no dosage reported) for RA flare [12A]. Her chronic medications without reported ADRs included hydroxychloroquine for RA, and bupropion, ursodiol, denosumab for primary biliary cirrhosis. Her rheumatologist increased her doses of prednisone and hydroxychloroquine and added quinacrine 100 mg daily for a week, but her rash did not improve. She was negative for lupus but positive for antinuclear antibodies. Her rash began to improve with discontinuation of abatacept and quinacrine.

Male fertility A meta-analysis of 84 studies reported DMARDs’ impact on fertility in males who were exposed to these drugs via maternal exposure. These studies evaluated 5986 pregnancies conceived during drug exposure or within 3 months of withdrawal [15MR]. There was no firm evidence or no risk from paternal exposure of abatacept, cyclosporine, tacrolimus, leflunomide, mycophenolate mofetil on male fertility.

Belatacept Belatacept (Nulojix®) is another selective T cell costimulation modulator that was approved by the FDA in 2011 for organ rejection prophylaxis in adults with kidney transplants [16S]. It has been known that belataceptbased immunosuppressive therapy carries an increased risk of acute T-cell-mediated rejection (aTCMR). Accordingly, studies have been conducted on belatacept-based regimens in patients with other organ transplantations to gain a better understanding of the pathogenesis of co-stimulation blockade-resistant rejections. Comparative studies A small pilot study used NanoString technique to compare the transcriptomic profiles of 14 tacrolimus-treated patients with aTCMR, 11 belatacept-treated patients with aTCMR, and 6 controls without rejection [17cE]. The study showed that 78 genes, especially T cell-associated genes, γ-interferon-inducible genes, and effector genes,

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had greater expression in the two aTCMR groups as compared to the controls. There were no differences in the immunomics of the kidney biopsy samples from the two aTCMR groups, as evidenced using similar classic immune markers of the innate and adaptive immune systems. These results suggest that there may be a final common pathway of allorecognition in aTCMR among different immunosuppressants. The prospective BELACOR single-arm, multi-center study compared the acute antibody-mediated rejection (ABMR) incidence post-kidney transplant in 49 patients treated with belatacept to 74 patients treated with calcineurin inhibitors (CNIs) [18C]. CNIs could be cyclosporine
tacrolimus at the physician’s discretion. All of the study patients were positive for preformed de novo donor-specific antibodies (dnDSA) within 1 year prior to their transplantation. Preformed dnDSA was defined as having the maximal mean fluorescence intensity between 500 and 3000. All patients underwent induction therapy with thymoglobulin and methylprednisolone at the beginning but received maintenance therapy with mycophenolate mofetil (MMF) and prednisone later. Those in the treatment group were treated with belatacept 10 mg/kg at day 1 and 5, week 2, 4, 8 and 12 and 5 mg/kg monthly in addition to maintenance therapy of MMF and steroid. Belatacept was not associated with increased risk of acute ABMR, similarly to CNIs; however, the belatacept-treated group had a significantly higher incidence of aTCMR, especially with steroidresistant rejections. The dnDSA occurrence was not significantly prevented by belatacept. The belatacepttreated group had significantly fewer infections (except for kidney allograft pyelonephritis) and less CVD ADRs. A post-hoc analysis of the two randomized, controlled, and partially blinded phase 3 trials (BENEFIT and BENEFIT-EXT studies) compared the rate of dnDSA development among more intensity-based belatacept (MI-), low intensity-based belatacept (LI-), and cyclosporine-based treatment in patients with kidney transplants over 3 years [19R]. The BENEFIT trial included patients transplanted with living or standard criterion deceased-donor kidneys. The BENEFIT-EXT trial included patients transplanted with an extended-criteria donor kidney based on the United Network for Organ Sharing expanded donor criteria or kidneys with an anticipated cold ischemia time 24 h, or kidneys donated after circulatory death. Positive dnDSA development was defined as a mean fluorescence intensity 2000. Post-hoc analyses based on data collection from the extended 7-year follow-up indicated that belatacept-based regimen can prevent dnDSA development more effectively than cyclosporine-based regimen. Patients who developed dnDSA against various specific HLA loci were 1.4% in the MI-based belatacept group, 3.5% in the LI-based belatacept group, and 12.1% in the cyclosporine-based group.

There were 2 classes of HLA loci listed in this post-hoc analysis, with each class including various subclasses of HLA loci. Class 1, for example, had HLA loci A, B, C and Class II included HLA loci DR, DP, and DQ, in addition to various combinations of classes I and II. dnDSA development was seen most often against HLA-DQ locus in all groups. dnDSA patients had categorized panel-reactive antibodies and 6 HLA mismatches; these differences were not statistically significant. A retrospective review on HLA immunoglobulin (Ig) isotype analysis testing in 330 patients from the previous BENEFIT (n ¼ 213) and BENEFIT-EXT (n ¼ 117) trials investigated IgM-to-IgG conversion difference among MI- and LI-belatacept and cyclosporine-treated patients [20R]. IgM-to-IgG conversion is an early sign of increased allograft risk. With similar baselines of pre-transplant IgM and IgG DSA-positive frequencies among all groups, IgM-to-IgG conversion was 2.8 times higher in the cyclosporine-treated group compared to the belatacepttreated groups (P ¼ 0.006). The belatacept-LI had a lower IgG-positive frequency (8%) than did the belatacept-MI (11%) (P < 0.001). Lung transplantation A 65-year-old female was treated with tacrolimus post-left lung transplantation [21r]. At month 11 posttransplant, she developed renal impairment secondary to tacrolimus toxicity and was switched to belatacept 10 mg/kg titration regimen for initial phase (days 1, 5, 14). She underwent bridging therapy of titrating tacrolimus and belatacept over 7 days. She developed fever and cough at day-25 post-belatacept treatment, and severe acute respiratory distress syndrome (ARDS) at day-27, requiring mechanical ventilation. The transbronchial biopsy revealed acute TCMR with negative DSA. She died from sepsis after 54 days of hospitalization. Pregnancy A 28-year-old female received a transplanted kidney secondary to polycystic kidney disease [22A]. She had unplanned pregnancies, which resulted in spontaneous abortions while on immunosuppressive therapies (azathioprine, tacrolimus, and mycophenolic acid). At 3 years post-transplant, she reported a third unplanned pregnancy while taking azathioprine, belatacept, and prednisone. Azathioprine was stopped and she continued only belatacept throughout her pregnancy. She gave birth to a healthy infant via caesarean section at 38 weeks gestation. A 36-year-old female underwent kidney transplantation secondary to solitary kidney and secondary focal segmental glomerulosclerosis [22A]. She had a planned pregnancy 4 years post-transplant while being treated with azathioprine, prednisone, and belatacept. She delivered a healthy baby at 37 weeks and 5 days gestation.

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Cyclosporine Cyclosporine (Sandimmune®) was first approved by the FDA in 1983 as a calcineurin inhibitor (CI) for posttransplantation of skin, kidney, liver, heart, lung, pancreas, small intestine, and bone marrow [23S]. It inhibits lymphocyte production in the Go- and G1 phases of the cell cycle, especially T-helper cells. Cyclosporine also inhibits lymphokine production and release. Modified cyclosporine (Neoral®, Gengraf®) with increased bioavailability was approved in 2000 [24S,25S]. In 2002, an ophthalmic formulation of cyclosporine (Restasis®) was FDA-approved to treat reduced tear reduction secondary to keratoconjunctivitis sicca in 2002 [26S]. Comparative studies A multi-centered, double-blind, parallel, randomized controlled phase 3 trial (VEKTIS trial, n ¼ 169) investigated efficacy and the safety profile of ophthalmic cyclosporine (CsA) in children from the age of 4 to younger than 18 years and diagnosed with vernal keratoconjunctivitis [27C]. Patients were randomized to receive cyclosporine 0.1% emulsion 1 drop into both eyes, either four times daily (high-dosed CsA) or twice daily (lowdosed CsA) or placebo for 4 weeks. The mean composite efficacy score was highest in high-dosed CsA as compared to the low-dosed CsA and placebo (2.06, 95% CI 1.67–2.45; 1.93, 95% CI 1.56–2.30; 1.34, 95% CI 1.02–1.67, respectively). Secondary endpoints of symptom improvement (i.e., reduction in photophobia, itch, and mucous discharge) were also observed most often in high-dosed CsA, followed by the low-dosed CsA and the placebo. Treatment-associated ADR frequency was similar across treatment groups, except for instillation site pain being the most frequent in the high-dosed CsA group. Other ADRs which occurred in one patient each from the high-dosed CsA were eye irritation, ocular hyperemia, blepharospasm, eyelid erosion, corneal leukoma, eyelid edema, and visual acuity reduction. A meta-analysis of 21 studies compared ADRs of tacrolimus with cyclosporine post-renal transplantation [28M]. Tacrolimus was superior in acute organ rejection (RR 0.1638, 95% CI 0.571–0.713, P < 0.001) and graft loss (RR 0.089, 95% CI 0.057–0.122, P < 0.001). Cyclosporine showed a lower trend of diabetes development (RR 1.891; 95% CI 1.522–2.350, P < 0.001). There was no difference in overall mortality between the two drugs. Administration A 19-year-old Iranian female underwent allogenic bone marrow transplant for acute myeloid leukemia (AML) [29A]. She had a history of food and seasonal allergies, and vancomycin hypersensitivity (reaction was not listed). She received her first 3 mg/kg dose of IV cyclosporine (Sandimmune) for GVHD prevention. Within

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the first 15 min of IV infusion, she developed acute respiratory distress, tachypnea, oxygen desaturation of 84%, tachycardia, flushing, and facial and gum swelling. The IV infusion was stopped, and her symptoms resolved within 1 h. The Naranjo score for cyclosporine was 8. The IV formulation was switched to the oral capsule the next day and the patient tolerated it well and without any reaction. Nephrotoxicity A meta-analysis of 12 trials was done to investigate 15 risk factors which are associated with CNI nephrotoxicity post-transplants [30M]. The analysis included 2 retrospective case–control studies and 10 cohort studies; the combined patients were 911 with CNI nephrotoxicity and 1892 without CNI nephrotoxicity. Three significant risk factors were identified: age, recipient zero-time arteriosclerosis, and CYP3A4*3/*3 genotype. A subgroup analysis showed that donor age was significantly correlated with CNI nephrotoxicity in Caucasian and Asian patients. Erythromelalgia A 56-year-old female was initiated on cyclosporine 100 mg oral three times daily for uncontrolled biopsyproven pemphigoid [31A]. She developed nervousness and shakiness at week 5 and these symptoms resolved when the cyclosporine dose was decreased to twice daily. At week 10, she started having redness, edematous, and burning pain on her left hand and to a lesser extent on her right hand. The symptoms were relieved when the patient exposed her hands to cold temperatures and worsened with heat or sun exposure. Her condition worsened over the next 7 weeks and erythromelalgia was diagnosed. Cyclosporine was decreased to 100 mg oral once daily and her symptoms completely resolved over the next 6 weeks. Invasive pulmonary aspergillosis A 79-year-old male was hospitalized for acute exacerbation of interstitial lung disease, which was treated with IV methylprednisolone 40 mg daily and oral cyclosporine 50 mg twice daily [32A]. He developed night sweats and productive sputum, went into acute respiratory distress, and required vasopressor support on hospital day 11. The diagnosis was Aspergillus fumigatus pneumonia with positive bronchial lavage culture, elevated serum β-D-glucan, and positive aspergillus galactomannan antigen. Empiric piperacillin–tazobactam and micafungin were switched to intravenous voriconazole therapy on hospital day 18 and he improved significantly. Drug-resistant epilepsy A 28-year-old man was initiated with monthly IV immunoglobulin G (IgG) with no specific dose listed

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and oral cyclosporine 550 mg daily post-bone marrow transplant for non-Hodgkin’s lymphoma [33A]. IgG was changed to prednisone when he developed GVHD of the liver. At 7.5 months post-transplant, his serum cyclosporine was supra-therapeutic (1467 ng/mL with a goal range of 100–200 ng/mL). He was then hospitalized for focal blindness and focal impaired awareness seizure. He had no past medical history or family history of seizure. Cyclosporine was changed to tacrolimus and his symptoms resolved. Central nervous system lymphoproliferative disorder A 77-year-old Caucasian Portuguese male was treated with oral cyclosporine 50 mg twice daily, oral MMF 500 mg twice daily, and oral prednisolone 5 mg daily [34A]. His immunosuppressive course of 16 years was complicated with a delayed graft function, CMV infection, prostate adenocarcinoma, CNI toxicity, recurrent UTIs, chronic graft failure. He was hospitalized for unspecific neurological symptoms (seizures, headache, gait disturbance, dysarthria, and confusion). A brain biopsy revealed EBV infection. The MMF dose was first reduced and eventually stopped and cyclosporine was switched to sirolimus. CNS lymphoproliferative disorder was suspected and rituximab was planned; however, the patient died before that. Condyloma acuminatum A 16-year-old Croatian female was receiving corticosteroid, cyclosporine, and azathioprine, post-kidney transplant [35A]. After 9 years, she was found to be positive for human papilloma virus and cervical intraepithelial neoplasia stage I. Two years later, she had multiple genital condylomas which were surgically removed. The treatment was unsuccessful and cyclosporine was switched to everolimus. Her genital condylomas disappeared over the next year.

Tacrolimus Tacrolimus (Prograf®) is another CNI FDA-approved drug for the prevention of rejection post-allogeneic liver, kidney, and heart transplantations, and moderate to severe atopic dermatitis as Protopic® ointment in 2006 [36S,37S]. Comparative studies A retrospective cross-sectional study of 66 patients treated with either cyclosporine (n ¼ 33) or tacrolimus (n ¼ 33) post-kidney transplant investigated modifiable and non-modifiable clinical and laboratory parameters of the patients’ treatment course [38c]. No specific dose range for either drug was reported. The tacrolimus group

had a numerically higher number of patients with A1c 7.2% at 3 years although there was no significant difference in graft survival rate between the 2 groups. The cyclosporine group had significantly higher blood pressure values at 6 months and 1 year and more patients with at least one acute rejection episode. A retrospective study of 125 French children treated with tacrolimus (initial dose range 0.1–0.5 mg/kg/day) or cyclosporine (initial dose range 1.0–12.7 mg/kg/day) post-kidney transplant revealed that the most common ADRs overall were renal disorders and infections while the tacrolimus group had a higher rate of GI disorders (abdominal discomfort, diarrhea, and non-specific symptoms) and neutropenia [39c]. A total of 5 patients treated with tacrolimus and 1 patient treated with cyclosporine developed lymphoproliferative disorders. Pain A 23-year-old Pakistanis male received MMF, tacrolimus titration (initial 0.6 mg/day, then increased to 1.5 mg/day) and voriconazole (no dose listed) to prevent GVHD after his allogeneic bone marrow transplant for AML [40A]. His serum tacrolimus level was therapeutic throughout (goal range 7.5–15 ng/mL). On day 15, he developed severe pain in his bilateral lower extremities and posterior superior iliac spine that was neuropathic in nature with stabbing and aching sensations— provoked by touching, walking, and standing; numbness and tingling extended to hands and feet. On day 37, tacrolimus was changed to cyclosporine and his pain gradually improved, which completely resolved upon initiation of long-acting nifedipine therapy. Condyloma acuminatum A 33-year-old male was treated with tacrolimus (5 mg/day), MMF (500 mg/day), and prednisone (3 mg/day) post-kidney transplant for 5 years [41A]. He had a history of 2 occurrences of urinary tract infection and reported sexual abstinence post-transplant. He was hospitalized with miction pain and urethral discharge secondary to multiple and diffuse papillary tumors in his penile urethra. A histological study indicated condyloma acuminatum. Tumors were resected and tacrolimus was switched to everolimus. No recurrence was observed over the following year. Parkinsonism A 51-year-old female was initially treated with MMF (500 mg/day) and methylprednisone (8 mg/day) [42A]. MMF was changed to tacrolimus (10 mg/day) due to an early graft rejection. After 7 days, she started to have disorientation and confusion which gradually worsened into tremor, mental disturbances, and resting tremor of all four limbs. She was diagnosed with severe, symmetric

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Parkinsonism. Amantadine, levetiracetam, and clonazepam therapies satisfactorily alleviated tremor. Tacrolimus was switched to sirolimus due to supratherapeutic level and her symptoms gradually resolved with no further treatment.

Sirolimus Sirolimus (Rapamune®) is an mTOR kinase inhibitor immunosuppressant, FDA-approved in 1999 for rejection prophylaxis post kidney transplant in patients 13 years of age, and in 2015 for lymphangioleiomyomatosis treatment [43S]. Comparative study A phase II/III trial compared the survival rates and safety profiles between a prednisone/sirolimus
photopheresis regimen (n ¼ 72) and a prednisone/sirolimus/ CNI regimen (n ¼ 66) for the treatment of cGVHD in patients who were treatment-naïve or early inadequate responders post stem cell transplants at 6 months (phase II) and 2 years (phase III) [44C]. Prednisone or prednisone-equivalent agent was initiated at 0.5–1 mg/ kg daily titrated to every other day. Sirolimus started at 2 mg daily (1 mg/m2 daily if weight < 40 kg) and was dosed to target trough level of 3–12 ng/mL. CNI was dosed to target trough level of 120–200 ng/mL for cyclosporine and 5–10 ng/mL for tacrolimus. There were no significant differences in failure-free survival and overall survival rates between the 2 groups; however, the prednisone/sirolimus
photopheresis group was better tolerated with a significantly lower mean increase in serum creatinine from baseline to 2 and 6 months (P ¼ 0.025 and 0.016, respectively), and a lower number of life-threatening infection episodes (P ¼ 0.682). Combination regimen A phase II prospective (GEIS) study investigated the efficacy and toxicity of gemcitabine–sirolimus in 27 patients with advanced soft tissue sarcoma failing standard therapy [45c]. Gemcitabine began at 10 mg/ m2/min IV on days 1 and 8, every 3 weeks, plus sirolimus 5 mg oral daily. Doses of both drugs were decreased based on toxicity levels. Although 44% of patients had a significant progress-free rate at 3 months and 20% at 6 months, the efficacy of this combination therapy was limited by toxicities of the drugs. The most frequent ADRs were neutropenia, leukopenia, infections, transaminitis, fatigue, and pneumonia. Life-threatening hypertriglyceridemia A 50-year-old male was treated with a regimen of sirolimus, prednisone, and twice weekly photopheresis regimen for cGVHD post-stem cell transplant [46A]. After

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the initiation of this regimen, his serum triglyceride level was noted between 300 and 400 over several years. He was treated with pravastatin and omega-3-fatty acid. He was then hospitalized for Mycobacterium abscessus systemic infection. During this hospitalization, photopheresis was switched to ruxolitinib due to IV access limitation. Three weeks after ruxolitinib initiation, he developed severe fatigue, nausea, and upper abdominal pain for which he was hospitalized. His serum triglyceride level was found to be 4000 mg/dL. He was treated with insulin drip and therapeutic plasma exchange. Both sirolimus and ruxolitinib were held. His serum triglyceride level decreased to 407 mg/dL on day 4 of hospitalization and he was discharged. It was suspected that this severe hypertriglyceridemia was caused by the combination of sirolimus and ruxolitinib. Ruxolitinib was switched to ibrutinib and sirolimus was switched to tacrolimus. The patient was instructed to follow a lowfat and low-carbohydrate diet. The patient’s serum triglyceride level remained between 94 and 270 mg/dL in the following year. Small bowel angioedema A 38-year-old Chinese female was treated with tacrolimus 3 mg twice daily, sirolimus 1 mg daily, and prednisone 25 mg daily, post-kidney transplant [47A]. She had no prior history of gastrointestinal illnesses or drug allergies. Abdominal pain started and worsened over 3 days post-operation. The serum tacrolimus and sirolimus levels were in the therapeutic range and a computed tomography (CT) scan showed diffuse small bowel wall thickening and ascites. Exploratory laparoscopy showed severe small bowel edema. Her symptoms relieved 48 h after sirolimus discontinuation and resolved after 7 days. She was discharged on maintenance tacrolimus, MMF, and prednisone. Infection-related deaths A case report of 2 infants who died of infections secondary to sirolimus therapy shows the need for antimicrobial prophylaxis in conjunction with immunosuppression in pediatric patients [48A]. In the first case, a 1-month-old Asian girl was treated with sirolimus 0.1 mg/kg/day for Kaposiform hemangioendothelioma (KHE). She developed bronchopneumonia after 2.5 months of treatment. Sirolimus was stopped and antimicrobial agents were initiated but the patient died 3 days later without a definitive cause of death due to the lack of postmortem examination. In the second case, a 4.5month-old Asian boy was treated with sirolimus 0.1 mg/kg/day for KHE. After 10 days of therapy, he was hospitalized for Mycoplasma bronchopneumonia. Despite antibiotic therapy, the infant died 11 days later.

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Temsirolimus Temsirolimus (Torisel®) was an mTOR inhibitor FDAapproved drug in 2007 for the treatment of advanced renal cell carcinoma. Since its approval, it has been studied in other types of cancers as well [49S]. Aspergillus pneumonia A 67-year-old male was treated with temsirolimus for renal cell carcinoma and brain metastasis for 2 months [50A]. He also received a week of IV steroid for brain edema. He developed persistent fever and worsening cough, which did not improve with antibiotics. He was eventually diagnosed with invasive pulmonary aspergillosis. He gradually improved with long-term antifungal therapy and switching from temsirolimus to pazopanib.

Everolimus Everolimus (Afinitor®) is an mTOR inhibitor FDAapproved drug for advanced renal cell carcinoma after failing sunitinib or sorafenib in 2009, for HER2-negative, hormone-receptor-positive advanced breast cancer in postmenopausal women in 2012, for progressive welldifferentiated non-functional, neuroendocrine tumors of gastrointestinal or lung origin with non-resectable, locally advanced or metastatic disease in 2016, and for subependymal giant cell astrocytoma associated with tuberous sclerosis without feasible surgical resection in 2018 [51S]. Comparative studies A retrospective study compared 1:1 (n ¼ 178) long-term outcomes over 45 months of tacrolimus— MMF
corticosteroids to tacrolimus—everolimus
corticosteroids starting on the day of surgery in patients post-liver transplant [52c]. MMF was dosed at 1–2 g daily based on serum creatinine and leukocyte counts. Prednisolone began at 1.0 mg/kg/day and was tapered to 25 mg/day and discontinued at month 3. Everolimus dose was introduced at 1.0 mg twice daily and adjusted to a target trough level of 3–8 ng/mL. When combined with everolimus, tacrolimus was dosed to obtain a target trough level of 3–5 ng/mL after everolimus was within the target range. When combined with MMF, tacrolimus target trough level was 6–15 ng/mL before 6 months and 5–10 ng/mL after 6 months. The two regimens had comparable efficacy (P ¼ 0.0891). Death was most commonly secondary to HCV-associated liver failure and CVD ADRs. A significantly greater number of patients in the everolimus group discontinued therapy due to ADRs which were most commonly infections (CMV and pneumonia). Other ADRs were hyperlipidemia, thrombocytopenia, edema, and oral sores.

Patients in the everolimus group had significantly better renal function. Combination regimen A phase I, prospective, open-label, single-center study determined the dose-limiting toxicities, maximum tolerated dose, pharmacokinetics, efficacy, and safety profile of an everolimus (10 mg daily)—metformin (500 mg twice daily) regimen [53c]. 8 patients with advanced solid malignancies resistant to standard therapy were initiated with everolimus alone for 7 days with their dose increased or decreased based on serum levels to reach therapeutic levels. Metformin was started at 500 mg twice daily on day 8 and the dose was increased 1850 mg twice daily as tolerated. Survival time ranged from 53 to 229 days. The study was terminated for 5 patients due to toxicity and 3 patients due to progressive disease. Dose-limiting toxicities were thrombocytopenia (n ¼ 2) and rash (n ¼ 1) (everolimus 10 mg and metformin 500 mg bid). Serious adverse events were sepsis (n ¼ 1), bile duct stenosis and obstructed esophagus (n ¼ 1), cholangitis (n ¼ 1), and liver abscess (n ¼ 1). The most frequent ADRs included epistaxis, fatigue, anorexia, coughing, dry skin, mucositis, skin rash, and stomatitis. Hyperglycemia also occurred during treatment. This drug combination increases serum everolimus levels but not everolimus exposure or serum metformin level. Three patients had stable disease with the combined regimen at week 9 but eventually terminated due to progressive disease or toxicity. A retrospective study investigated the efficacy and safety of everolimus (10 mg/day) and exemestane (unspecified dose) therapy in 264 patients with positive hormone receptor and negative human epidermal growth factor receptor 2 metastatic breast cancer (HR +/HER-MBC) over 5 years [54C]. Everolimus doses were decreased to 5 mg/day for toxicities grade 2 and greater or temporarily held at the same level for milder ADRs. The treatment outcomes were 39.8% partial responses, 33.3% disease stabilizations, 26.9% disease progressions, and no response. Diabetes and previous chemotherapy for metastatic disease were linked to a worse outcome and the development of mucositis was associated with long-term survival. ADRs included thrombocytopenia and neutropenia, both of which were mild (G1–3) and no G4 events were observed. The most frequently reported non-hematologic toxicities were stomatitis, fatigue, rash, and diarrhea. G3–4 events were mainly in patients treated as third-line therapy. A prospective observational study investigated the safety and efficacy of everolimus 10 mg/day and exemestane 25 mg/day in 50 Lebanese patients with hormonepositive advanced breast cancer over 2.5 years [55c]. Progress-free survival was 5.2
4.1 months (range 1–19.9) with a better response in Her-2 positive patients

IMMUNOSUPPRESSIVE DRUGS

(P ¼ 0.130). There was a partial response in 14% of the patients. Stomatitis and myalgia were the most common dose-dependent ADRs. Other less common ADRs were skin rash, hyperglycemia, and pneumonitis. Endothelial dysfunction A prospective observational study compared endothelial function post-kidney transplant in 44 German children aged 6–18 years, treated with an everolimus-based regimen (n ¼ 22) vs those on MPA-based regimen (n ¼ 22) [56c]. Everolimus was dosed to obtain a target trough range of 3–6 ng/mL in the first 6 months and 2–5 ng/mL thereafter; MMF dose was not listed. Both groups had similar rates of hypertension. The everolimus group had endothelial dysfunction (elevated carotid intima-media thickness, lower angiopoietin-1 and higher angiopoietin-2 levels) compared to healthy children and exhibited a twofold decrease of skin microvascular function compared to the MMF group (P < 0.001). Noninfectious pneumonitis A 62-year-old Portuguese male was treated with everolimus 0.25 + 0.5 mg/day, cyclosporine 25 + 50 mg/day, and prednisolone 10 mg/day post-heart transplant for 17 years [57A]. He also had a history of stage 3 chronic kidney disease, severe arterial hypertension, diabetes mellitus, and dyslipidemia. His serum everolimus level was therapeutic. He was hospitalized with right pleuritic chest pain, fever, dry cough, and worsening dyspnea for 5 days. All cultures and infective biomarkers were negative and the patient did not respond to antimicrobial therapies. Due to the suspicion of everolimus-induced pulmonary toxicity, everolimus was discontinued, then reinitiated out of the concern for acute organ rejection. Everolimus was then stopped again during his hospital course and as of day 9 of his hospitalization, the patient was only maintained on cyclosporine. On hospital day 43, he developed Pseudomonas aeruginosa ventilatorassociated pneumonia which was treated with antibiotics for 7 days. He gradually improved and was discharged on day 64. His immunosuppressant therapy was changed to cyclosporine, MMF, and prednisolone. Another 66-year-old man was treated with prednisolone, MMF, and tacrolimus (no doses listed) post-kidney transplant [58r]. After a year, tacrolimus was switched to everolimus 10 mg/day due to chronic allograft nephropathy. He remained on this new regimen for the next 5 years but was then hospitalized with shortness of breath, dry cough, and pleuritic chest pain. His symptoms progressively worsened despite empiric antibiotic treatment for community-acquired pneumonia. A noncontrast computed tomography revealed bilaterally multifocal ground-glass opacities. After ruling out other possible causes, he was diagnosed with mTOR inhibitorassociated pneumonitis and everolimus treatment was

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switched back to tacrolimus. His symptoms improved gradually over the next 5 days and no complication was observed with his 1-month follow-up. Stomatitis A retrospective report of 135 studies of 20 915 patient treated with everolimus 5–10 mg/day for solid tumors and tuberous sclerosis complex, temsirolimus 5–25 mg/week for advanced solid tumors, or ridaforolimus 12.5–37.5 mg/dose for solid tumors [59R]. Low-grade stomatitis frequency was highest with ridaforolimus treatment (54.76%), followed by temsirolimus (27.02%) and everolimus (25.07%). Lung injury A 66-year-old female underwent right nephrectomy due to a right renal tumor [60A]. Two years later, she had metastatic renal cell carcinoma and primary adenocarcinoma in the lung that was treated with sorafenib. Everolimus was added due to the slight enlargement of left pulmonary nodules 2 years later. No specific dosing was reported. Over the next 4 months, serum carcinoembryonic antigen (CEA) concentrations trended up to the highest level of 25.7 ng/mL and serum C-reactive protein levels also slightly elevated. She developed a grade 2 dry cough. Everolimus-induced lung injury was suspected and stopped. At her 2-month follow-up, serum CEA concentration had dropped to 5.9 ng/mL and ground-glass opacities on the chest CT had disappeared. Bone marrow edema A 62-year-old obese Caucasian female (BMI 42.9 kg/ m2) was treated with intramuscular octreotide and everolimus 10 mg/day for grade 1 pancreatic neuroendocrine tumor (pNET) with metastasis to the liver [61A]. After 6 months, she developed right foot pain and edema with difficulty walking for a week. Her doppler ultrasound was unremarkable, and duloxetine, cyclobenzaprine, methylphenidate, oxycodone, docusate, lorazepam, and ondansetron were initiated. Two weeks later, she presented with moderate bilateral lower extremity edema and she was instructed to wear compression stockings and elevate her legs. Four weeks later, the MRI of her left leg revealed severe marrow edema and compression fracture of the left calcaneus. Everolimus was discontinued and her symptoms completely resolved less than 2 weeks later. Terminal iliac ulcers A 40-year-old male was initially treated with tacrolimus–MMF–steroid regimen post-heart transplant without induction therapy (no dosing listed) [62A]. The MMF was switched to everolimus and steroid use was weaned off after a year. The everolimus dosage was regularly adjusted to obtain a target serum level of 6 ng/mL

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with an average dose of 3 mg/day. Oral mucositis and stomatitis developed with everolimus therapy. Two years later, he was hospitalized for ileitis, which was treated with antibiotics and improved over 19 days. He was readmitted 2 days after being discharged for the same condition. His colonoscopy showed multiple ulcers in the terminal ilium and a histologic study ruled out lymphoproliferative disorder. The everolimus dose was switched back to MMF and the ulcers gradually healed. Severe hypertriglyceridemia A 42-year-old female was treated with everolimus for her tuberous sclerosis complex-related angiomyolipomas for 6 months [63r]. She developed grade 4 hypertriglyceridemia with serum triglyceride 6000 mg/dL and acute pancreatitis with elevated liver enzymes and lipase 350 units/L, amylase 600 unit/L, blood glucose 420 mg/dL, and a glycohemoglobin level (HbA1c) of 15%. She was managed with parenteral insulin infusion and supportive care. Fenofibrate was added to her everolimus therapy and her triglyceride levels remained normal. Erythema nodosum A 13-year-old female was treated with everolimus for tuberous sclerosis complex for 4 months [64A]. Her other chronic medications were lamotrigine and fluoxetine. During her physical examination, she had a tender, erythematous, indurated 6  4 cm area on her left shin with 2 tender pink subcutaneous nodules on her lateral thigh. A skin biopsy showed erythema nodosum. This skin condition worsened after an increase of the everolimus dose to adjust for a subtherapeutic serum level; therefore, the everolimus dose was then decreased much further in addition to a erythema nodosum treatment. With the decrease in the everolimus dose, her skin condition improved within 2 weeks. Eyelid edema A 77-year-old Caucasian female was taking tacrolimus and everolimus after a cardiac transplant and the resection of a carcinoid pulmonary mass [65A]. Soon after everolimus initiation, she started having eyelid and lower extremity swelling. Although the serum everolimus level was therapeutic, the drug was stopped and her swelling improved. On rechallenge, only her eyelids swelled with skin overhanging the lashes causing eyelid heaviness and impaired vision. Everolimus therapy was continued and an upper eyelid blepharoplasty was performed to remove excess eyelid tissue. Pathology revealed moderate edema in the dermis and mild vascular dilation. The procedure was a success with symptom resolution.

Glatiramer Glatiramer acetate (GA) (Copaxone®, Glatopa®) is an immunosuppressant approved by the FDA in 1996 for the treatment of multiple sclerosis (MS) (relapsing, relapsing–remitting). It is thought to induce and activate suppressor T-lymphocytes in addition to its ability to interfere with the antigen-presenting function of certain immune cells [66S]. Ulnar neuropathy A 30-year-old female was treated with subcutaneous GA for MS [67r]. She complained of left ulnar nerve pain as an “electric shock” sensation immediately after injection in the posterior side of her left arm. Physical examination revealed intrinsic muscle weakness of her left hand and sensory deficit in the ulnar side of that hand, and axonal neuropathy was confirmed. Local mechanical damage to the ulnar nerve was suspected to be directly attributed to the injection. Long-term outcomes A prospective observational study followed patients with MS treated with GA (n ¼ 144) and interferon-β (IFN-β) (n ¼ 150) to investigate the long-term outcomes of these therapies [68R]. No dosing was reported. Median times on the treatment were 2.6 years for IFN-β and 4.7 years for GA, while some patients remained on these therapies for over 10 years. The mean ages at the time of treatment initiation were 35.11
9.62 years
standard deviation for IFN-β and 37.52
10.04. Both therapies had similarly limited disease progression and the older patients had a numerically slightly better disease course with IFN-β treatment. No specific age range for these older patients was reported. Patients treated with GA tended to remain on therapy significantly longer. Altered gut microbial composition A prospective study of 186 patients diagnosed with relapsing MS [69R]. The patients were treatment-naïve (n ¼ 75), treated with dimethyl fumarate (DMF) (n ¼ 33), and GA (n ¼ 60). No specific dosing was reported. GA and DMF therapies both altered gut microbial composition with different patterns of increase or decrease in certain microbial families such as genus Prevotella, genus Sutterella, or order Clostridiales, etc. These increases and decreases in microbial taxa in turn changed the absorption and metabolism pathways of various nutritions. Pregnancy An observational study among 5042 pregnancies in European women treated with GA for MS showed 138 congenital anomalies not significantly associated with the drug [70R]. No specific dosing was reported. Using

IMMUNOSUPPRESSIVE DRUGS

a ratio of observed-to-expected cases, the risk of congenital anomalies was similar to that expected in the general population. Injection-site reaction An in-vitro model (hyaluronic acid filled cartridges mimicking subcutaneous space) and an in-vivo model (mice) were used to study the mechanisms for injection-site reaction (i.e., injection site mass, erythema, atrophy) and draining lymph nodes (i.e., lymphadenopathy) associated with GA injection [71H]. The in-vitro model showed that glatiramer–hyaluronic acid aggregates at the injection site and slows drug release into the system over 3 days. On day 3, approximately 30% of the drug was found at the injection site. The in-vivo model showed that the drug traveled to the draining lymph node and remained there for over 4 h. A prospective observational study investigated postinjection reactions (PIR) of GA in patients with relapsing–remitting multiple sclerosis [72R]. Typical reactions were palpitations, dyspnea, tachycardia, bronchospasm, and urticaria. Atypical symptoms were abdominal cramps, nausea/vomiting, diarrhea, shivering, fever, and other uncommon symptoms. Patients either received SQ 20 mg GA (n ¼ 97) or 40 mg GA (n ¼ 173). The 40 mg dose was significantly associated with atypical post-injection reactions. In this group, 22% reported atypical PIRs, of which 15% had recurrent reactions, and 8.1% experienced both typical and atypical PIRs. The 20 mg dose had only 2.1% responded with atypical PIRs.

Leflunomide Leflunomide (Arava®) is a prodrug pyrimidine synthesis inhibitor approved by the FDA in 1998 for active RA in adults [73S]. Comparative study A meta-analysis of 6 randomized controlled trials compared the efficacy and tolerability of leflunomide (10 or 20 mg) with tacrolimus (1.5–2 mg or 3 mg) in 1510 patients with RA or psoriatic arthritis [74M]. The frequency of patient withdrawals due to the lack of leflunomide efficacy was lowest with the 20 mg dose compared to the 10 mg dose and the same dose-dependent withdrawal rate was observed in tacrolimus groups. There was no significant difference in therapy withdrawals due to ADRs among groups and there were fewer ADRs in the placebo group compared to the treatment groups. Leflunomide was more efficacious but less tolerable than tacrolimus for RA treatment.

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Pregnancy A retrospective population-based cohort study with prospective follow-up investigated adverse pregnancy outcomes in pregnant Canadian women treated with leflunomide and antirheumatic drugs for various immune diseases (i.e., RA, MS, systemic lupus erythematosus, and others) [75r]. 51 patients were taking leflunomide during the first trimester (mean exposure 51.2 days
5.2) and 21 during the second/third trimesters (46.1 days
7.8). Leflunomide exposure during pregnancy was found to have no significant association with adverse outcomes (major congenital malformations, prematurity, low birth weight, spontaneous abortions). Pulmonary arterial hypertension A case report of 4 patients treated with leflunomide (10 or 20 mg/day) for RA (n ¼ 2), psoriatic arthritis (n ¼ 1), and undetermined diagnostic criteria for systemic sclerosis or lupus (n ¼ 1) [76A]. Duration of the drug treatment was between 7 and 120 months. Following treatment, all patients presented with grade II–IV dyspnea, increased pulmonary vascular resistance, and decreased cardiac output. Leflunomide was stopped and 3 patients underwent a cholestyramine washout period. All patients improved in 2–4 months. Gross hematuria A 70-year-old female was taking daily leflunomide, sulfasalazine, prednisolone, and monthly golimumab for her RA [77A]. No specific dosing was reported. She presented with a gross hematuria and some difficulty urinating for 5 days. Her previous occurrence of these symptoms 4 months ago resolved spontaneously. Normochromic normocytic anemia was also present at this time. A flexible cystoscopy revealed abnormal neovascularization patterns and the bleeding from these vessels was secondary to the drug-induced thrombocytopenia. Leflunomide was stopped and there was no recurrence of her symptoms. Drug–drug interaction A mouse model study showed that leflunomide decreased methotrexate and its toxic metabolite 7-OH-methotrexate levels in bile excretion, while increasing their concentrations in the liver, kidneys, and plasma. This action occurred via leflunomide’s effect on efflux transporters in these organs through PPARα genes [78H]. Pyomyositis A 77-year-old female was taking leflunomide and certolizumab pegol for her 29-year history of RA [79A]. She was hospitalized for a second episode of acute onset severe right hip pain worsened by weight bearing,

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36. DRUGS THAT ACT ON THE IMMUNE SYSTEM

following a previous episode of septic arthritis. An MRI did not show marrow, joint, or bone involvement. Frank pus, discharged from multiple upper thigh muscles (adductors and gluteus medius) during exploratory surgery, was cultured and resulted negative, possibly due to the initial antibiotic therapy; however, blood culture grew Enterobacter cloacae. Pyomyositis was diagnosed and the patient recovered with antibiotic treatment.

Teriflunomide Teriflunomide (Aubagio®) is another pyrimidine synthesis inhibitor first FDA-approved in 2012 for the treatment of patients with relapsing MS [80S]. Teriflunomide is an active metabolite of leflunomide [81r].

steatosis and days later, her peak serum triglyceride level was 5942 mg/dL. Fenofibrate and pitavastatin were initiated and her serum triglyceride level eventually decreased to 82 mg/dL after a week. Lactose intolerance Teriflunomide tablets contain lactose as an excipient, which can induce GI symptoms secondary to lactose intolerance [81r]. An observational retrospective review of 100 patients without prior history of lactose intolerance at a single center revealed mild-to-moderate diarrhea in 14 patients occurring after teriflunomide 14 mg/day initiation. Their symptoms gradually resolved within a month. This review also showed 4 patients continued to have daily diarrhea without relief from antispasmodic agents and their lactose breath tests were positive.

Liver toxicity A meta-analysis of 13 comparative studies (IFN-β vs teriflunomide, IFN-β/teriflunomide vs another diseasemodifying therapy) investigated drug-induced liver toxicity [82M]. No specific dosing was reported. An indirect comparison analysis showed no statistically significant differences between teriflunomide and IFN-β treatment (OR 1.09, 95% CI 0.02–2.16). Pregnancy A Danish cohort study with prospective follow-up of 13 pregnant women treated with teriflunomide and 18 male partners treated with this drug [83c]. No drug dose was reported. Normal healthy livebirths occurred with all the treated men and 2 normal healthy livebirths plus 11 elective abortions occurred with the 13 treated women. A 28-year-old female was treated with teriflunomide 14 mg/day for MS [84r]. She had an unplanned pregnancy and the drug was stopped at 6 weeks of gestation. She did not undergo accelerated elimination therapy and was not on any therapy for MS. She gave birth to a termed, healthy, normal baby. Teriflunomide was resumed after delivery. Severe hypertriglyceridemia A 44-year-old female with normal body mass index (BMI) was diagnosed with relapsing–remitting MS (RRMS) for 8 years. She was initially treated with IFNβ-1a and later switched to teriflunomide 14 mg/day due to hypertransaminasemia [85A]. GA was then switched to teriflunomide due to severe injection-site cutaneous reactions. After 2 years on teriflunomide, her serum cholesterol level was 247 mg/dL for which she was advised lifestyle modification. A year later, her serum triglyceride was 981 mg/dL. Her liver enzymes gradually elevated and she was found to have hepatic

Progressive multifocal leukoencephalopathy (PML) A 36-year-old female was initially treated with IFN-β and then natalizumab for her MS for 10 years [86A]. She was switched to teriflunomide due to John Cunningham (JC) virus detection. No PML was detected. At 3 months later, a brain MRI revealed a new nonenhancing lesion in left cortical–subcortical temporal lobe that was suggestive of PML. She also developed anomic aphasia. Her clinical manifestation worsened despite discontinuation of teriflunomide and accelerated elimination procedure. No JCV DNA was detected in cerebrospinal fluid. Steroid therapy was started. Her clinical condition eventually improved. The differential diagnosis was PML-immune reconstitution inflammatory syndrome vs MS reactivation. Palmar pustular psoriasis A 52-year-old female with a 13-year history of RRMS was initially treated with SQ IFN-β-1a 44 mcg, which was later switched to teriflunomide (no dose reported) due to injection-site pain [87A]. Six months later, she developed painful and disabling extensive bilateral palmar pustular lesions. Lesions did not improve with local steroids and topical and oral antibiotics. Teriflunomide was stopped and cholestyramine was started. All lesions completely healed after a month and there was no recurrence. Chinese population A sub-analysis of the phase 3 TOWER trial studied the efficacy and safety of teriflunomide among adult Chinese patients with a history of relapsing MS (7 mg dose, n ¼ 51; 14 mg dose, n ¼ 43; placebo, n ¼ 54) [88R]. There was a trend in dose-dependent efficacy (statistically significant for 14 mg and not for 7 mg dose). The drug at both doses was well tolerated with no significant differences in

IMMUNOSUPPRESSIVE DRUGS

serious ADRs among groups. The most common ADRs were neutropenia, elevated alanine aminotransferase, and alopecia. Hair loss A prospective observational study of 38 patients treated with teriflunomide 14 mg/day (n ¼ 36) and 7 mg/day (n ¼ 2) investigated the hair loss progression over 2 office visits [89c]. The median onset of hair loss was 77 days since drug initiation and the median follow-up time was 270 days. 62% of these patients were taking other drugs that also experienced hair loss. It was noted that the patients tended to report their severity of hair loss to a greater degree than did their health care providers. Hair loss pattern ranged from mild, diffuse thinning, to loss of large batches of hair. One patient had irreversible loss of their eyebrows. Two patients discontinued therapy due to hair loss. Another retrospective chart review of 119 Canadian patients treated with teriflunomide revealed alopecia as the most frequent adverse event, followed by diarrhea and nausea [90c]. No specific dosing was reported. Gastrointestinal adverse events were the most common reason for drug discontinuation and partial efficacy being the second most common. Teeth loss A case report of 3 patients with long histories of MS had mandibular pain followed by multiple teeth loss (4–12 teeth) with no recent trauma after 4–12 months of teriflunomide therapy [91A]. No specific dosage was reported. The first patient had a history of dental cavities and teeth loss and an examination revealed diffuse alveolar atrophy and periapical bone loss in several residual roots. The second patient had moderate chronic periodontitis while the third patient had no available dental record. Teriflunomide was stopped in all cases and an accelerated elimination procedure with cholestyramine was started.

Dimethyl fumarate Dimethyl fumarate (DMF) (Tecfidera®) is an immunosuppressant via the nuclear factor (erythroid-derived 2)like 2 (Nrf2) pathway. It was approved by the FDA in 2013 to treat relapsing forms of MS [92S]. Observational study An open-label, multicenter prospective study (FOCUS) of 22 pediatric patients with MS aged from 10 to 17 years used an escalated-dosing strategy of DMF (120 mg twice daily for the first week, then 240 mg twice daily thereafter) to study its safety and

447

efficacy over 24 weeks [93c]. DMF provided significant reduction in new lesions and relapses. ADRs occurred in 91% patients, most commonly GI events and flushing which either resolved spontaneously or therapeutically. Two patients stopped treatment due to ARDs. None experienced severe lymphopenia. A prospective study assessed predictors of hematological abnormalities in patients with MS treated with either DMF (n ¼ 405) or fingolimod (n ¼ 300) for at least a year [94c]. The DMF group had a lower baseline lymphocyte count and had a significantly higher risk for lymphopenia grade 2 (P < 0.0001). Additionally, female patients treated with fingolimod or natalizumab were at higher risk for at least grade 3b lymphopenia. Switching between DMF and fingolimod treatments did not improve lymphocyte and leukocyte counts. A reduction in the fingolimod dose helped increase lymphocyte count but increased disease activity in 25% of the patients. Blood samples of 55 patients with RRMS treated with either DMF or fingolimod or neither (control group) were collected and examined for lymphocyte characteristics [95c]. All patients treated with fingolimod for more than 1 year had severe lymphopenia, while 40% of patients in the DMF group had less than grade 3 lymphopenia. Both treatments resulted in lower CD3 + cell counts while CD4 + cell counts were lower in the fingolimod group. The DMF group had significantly lower central memory CD4 + and effector memory cells in the CD8 + cell group along with a lower number of Th17 cells. The fingolimod group had a significantly higher fraction of CD196 + cells within the within CD4 + cell group and lower frequency of Tfh cells. CD19 + B cell counts were lower in the fingolimod group and distributed differently in the 2 treatment groups. The distribution of monocytes, national killers, dendritic cells was also different between the 2 groups; additionally, lymphopenic patients treated with DMF had a different cytokine profile as compared to those in the fingolimod group. A prospective study of 720 DMF-treated Italian patients with MS indicated that DMF (no dosage included) was an effective treatment with an overall significant 63.2% absolute relative risk (ARR) reduction, 70% in treatment-naïve group, 75% efficacy switch group, and 9% in safety switch group (all P values < 0.0001) [96C]. The study noted that 81.8% of patients were relapse-free and 70% remained on DMF at 24-month follow-up. Therapy discontinuation was associated with ADRs (i.e., GI symptoms, lymphopenia, others) and age. Most frequent abnormal laboratory value was grade 1 lymphopenia. Females tended to have more GI ADRs than males (OR 2.19, 95% CI 1.52–3.15, P < 0.0001). Another observational retrospective 2-year study looked at DMF safety profiles in 253 Danish patients with

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RRMS [97C]. 27.7% of patients discontinued DMF, with the majority being due to ADRs. The three major ARDs are GI disturbances, flushing, and lymphopenia. Comparative studies An observational retrospective review with prospective follow-up of 903 adult Italian patients with RRMS was conducted to investigate 24-month discontinuation rate and reasons for withdrawals from teriflunomide and DMF [98C]. A greater number of patients discontinued DMF within 12 and 24 months. A lack of efficacy such as experiencing a new relapse or new brain lesion detected was the most common withdrawal reason and was observed more frequently among DMF group, although this number was not statistically significant. The most common ADR was GI disturbances for both drugs. A similar retrospective cohort study of 346 French patients with a history of RRMS compared the efficacy and safety of DMF and teriflunomide [99C]. No specific dosage was reported. The adjusted DMF efficacy rate was significantly better than that of teriflunomide (ARR 0.06 vs 0.21, respectively, P ¼ 0.03). A significantly greater number of DMF-treated patients reported certain ADRs (P < 0.001) (i.e., lymphopenia, flush, GI disorders) although the reverse was seen with alopecia and hypertension. Accordingly, the DMF group had a numerically higher discontinuation rate (P ¼ 0.58). A phase I, randomized, double-blind, placebocontrolled, multicenter study (PREVENT) investigated the efficacy of bismuth subsalicylate 524 mg, taken twice daily in alleviating GI-related ADRs of DMF (120 or 240 mg twice daily) [100C]. A total of 175 adults on an 8-week course of 240 mg DMF twice daily were randomized to receive either bismuth subsalicylate 524 mg twice daily or placebo for 4 weeks. The frequency of GI ADRs was similar between the 2 groups. However, the severity of these symptoms was greater for diarrhea (P ¼ 0.0500) and significantly lower for flatulence (P ¼ 0.0219) with bismuth subsalicylate therapy. A randomized, open-labeled, controlled trial (APEX) of 115 Japanese patients diagnosed with RRMS were randomized (1:1) to receive DMF 240 mg twice daily or placebo for 72 weeks [101C]. The DMF group had more ADRs (i.e., flushing and related events, GI events, infection, cardiovascular events, elevated AST and ALT) with the earliest symptom being flushing. The incidence of flushing and related symptoms, and lymphopenia caused by DMF, was lower compared to previous studies in mostly Caucasian patients. A comparative retrospective chart review of 737 adults treated with DMF and 535 adults treated with fingolimod to treat MS over a period of 24 months from therapy initiation [102C]. The discontinuation rate was significantly

higher and occurred significantly earlier in the DMF group (OR 1.55, 95% CI 1.21–1.99, P < 0.001; HR 1.48, 95% CI 1.25–1.74, P < 0.001, respectively). Intolerability was the primary reason for therapy discontinuation for both groups (GI ADRs with DMF and headaches with fingolimod) and more so with DMF. Both therapies had similar efficacy. Delayed hypersensitivity reaction A 46-year-old female was treated with several agents for RRMS. She was switched to DMF 240 mg twice daily for its oral dosing convenience [103A]. Several hours after the first dose, she developed generalized confluent pruritic wheals. She was treated with IV steroid and antihistamine in the emergency department. A skin prick test was negative, but a lymphocyte transformation test was positive. As a result, DMF was switched to GA. Erythema nodosum A 29-year-old female was taking DMF 240 mg twice daily for 6 years to treat MS [104A]. She took no other medications. She developed mildly painful, erythematous, ecchymosis-like lesions on her bilateral lower limbs 9 months prior to her appointment. These lesions were diagnosed as erythema nodosum and suspected to be secondary to DMF; however, she refused to discontinue DMF. Diffuse dermatophytosis A report described 2 cases of a 60-year-old male and a 47-year-old male was treated with DMF for RRMS, who both developed biopsy-proven tinea with diffuse multifocal erythematous scaly patches with rounded edges in various areas on the bodies [105A]. No specific DMF dosages were reported. Both patients presented with lymphopenia, one to a moderate degree and the other to a milder extent. Their symptoms improved with DMF discontinuation and a months-long course of oral antifungal therapies. Deep venous thrombosis (DVT) A 36-year-old male had an unprovoked extensive DVT in his right popliteal and posterior tibialis veins 12 months after his 240-mg twice daily DMF initiation [106A]. The patient’s family and social histories were noncontributable. He was treated with warfarin with the continuation of DMF therapy. The authors suspected DMF treatment to be associated with the patient’s DVT occurrence. Lymphopenia A 39-year-old female was initially treated with IFN-β which was interrupted due to her pregnancy [107A]. DMF was started (no dosage reported) after her delivery

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and over the next 3 months, her lymphocyte count gradually decreased to 600/μL (grade II lymphopenia). She was hospitalized with confusion, mood fluctuation, fever, headache, and pharyngodynia. She was diagnosed with HSV-1 encephalitis and treated with IV acyclovir for 3 weeks. She was left with mild short-term memory deficit and sporadic inadequate affectivity. Neuromyelitis optica spectrum disorder (NOSD) A 48-year-old Polish female with a history of hypertension, Helicobacter pylori gastritis, and dyslipidemia was hospitalized for non-specific, non-enhanced, subcortical and periventricular lesions on an MRI and vision loss in her left eye [108A]. Despite the high-dose IV steroid therapy, her vision loss persisted. The cerebral spinal fluid analysis was normal and an angio MR was unremarkable. Three months later, she developed left-sided weakness with left cranial nerve VI and right cranial nerve VII palsies, which resolved with the high-dose IV steroid. IFN-β-1b therapy was started but later switched to 240 mg twice daily DMF due to a lack of efficacy. She developed a severe relapse 3 months after starting the DMF treatment and was diagnosed with NMOSD with positive serum anti-AQP4 antibodies. The DMF treatment was then switched to azathioprine and her clinical presentation subsided with some remaining physical disability. Bone marrow edema A 54-year-old female was treated with DMF for her history of RRMS for a year [109A]. No DMF dosage was reported. She complained of pain and inability to straighten left knee after playing hockey, with no prior trauma reported. An MRI showed an un-displaced fracture of the femoral condyle, extensive bone marrow edema, and a mild medial meniscal tear. The previous edema was reduced but new edematous locations appeared 2 months later. She developed a non-traumatic fracture of the left navicular 7 months later. A profound lymphopenia gradually developed. Bone marrow edema progressively spread throughout her lower extremity and new fractures appeared. DMF-associated profound lymphopenia was suspected to the cause of her bone marrow edema. DMF was then switched to natalizumab and then denosumab. Her clinical presentation improved and did not recur.

Mycophenolic acid Mycophenolic acid (MPA) is an immunosuppressant that inhibits the de novo pathway of guanosine nucleotide synthesis without incorporation in DNA. It was approved by the FDA in 2009 for prophylaxis of organ rejection in kidney transplants in combination with

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cyclosporine and corticosteroids [110S]. It is available in 2 forms: the prodrug form of mycophenolate mofetil (MMF) marketed as Cellcept®, and mycophenolate sodium (MPS) marketed as Myfortic® [116A]. Comparative studies A meta-analysis of 10 studies compared the safety and efficacy of tacrolimus–sirolimus vs MMF–tacrolimus in patients with a history of kidney transplants [111M]. No specific dosages were reported. No significant differences in efficacy (rate of delayed graft function, graft survival) or some ADRs (infectious complications, anemia, or seroma) occurred between the treatment groups. The MMF–tacrolimus combination was found to have significantly lower rates of diabetes, hyperlipidemia, and lymphocele. Observational studies A retrospective pharmacovigilance disproportionality analysis used the Japanese Adverse Drug Event Report database to compare the safety profiles between Japanese adults (n ¼ 10 272) and children (n ¼ 1322) treated with MMF for kidney transplants [112C]. Data analysis showed that 45.8% of the ARDs in adults were associated with MMF vs 42.6% in pediatrics. Among the top 10 most frequent ADRs identified in each group, while CMV infection, polyomavirus-associated nephropathy, and CMV-positive were significantly identified in adults, these were not significant in pediatrics. None of the top 10 ADRs in pediatrics were detected as signals. A longitudinal study of 190 patients treated with MMF post-kidney transplant showed no significant association in BMI changes between IMPDH1 rs 2 278 293 and IMPDH2 rs11706052 genotypes. For IMPDH1 rs 227 894, allele G was linked to significantly slower BMI gain in dominant inheritance [113C]. Within the first 6 months of MMF therapy, at least 2% of G allele carriers were underweight and at least 10% of them had BMI < 20 kg/m2 after 1 year of therapy. This study shows that MPA derivatives can potentially affect BMI via its influence on body-fat content. Diarrhea A retrospective observational population-based study investigated cryptosporidiosis in 210 immunodeficient French patients due to HIV infection or immunosuppressant-induced over 3 years [114c]. 68% patients treated with MMF alone or in combined therapy for their history of solid organ transplant and symptomatology were found to have cryptosporidiosis within the first 6 months of their therapies with a mortality rate of 6%. Cryptosporidium parvum and C. hominis were the most common organisms in these cases.

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A case report of 2 patients both treated with MMF, tacrolimus, and steroid post-kidney transplants described the onset of watery diarrhea (5–6 episodes/ day) 6–13 months after MMF initiation [115A]. The first patient had 1080 mg/day enteric coated mycophenolate sodium (EC MPS), 4 mg/day tacrolimus, and 4 mg/ day methylprednisolone. The second patient had 1080 mg/day EC MPS, 1 mg/day tacrolimus, and 5 mg/ day prednisone. Their diarrhea was accompanied by abdominal cramps and resulted in significant weight loss. Blind duodenal biopsies showed a combination pattern of villous atrophy and intraepithelial lymphocytosis that differed from genuine celiac disease by concurrent epithelial cell apoptosis and the absence of lymphoplasmacytic mucosa infiltrates. A reduction in MMF dose did not resolve clinical symptomatology. MMF was switched to azathioprine and the diarrhea was resolved a week later. A 37-year-old female was treated with MMF for 2 years for systemic lupus erythematosus (SLE) and lupus nephritis [116A]. No drug dosage was specified. She presented with diarrhea that had been ongoing for 4 months. MMF treatment was previously switched to EC MPS 2 months prior to presentation but her diarrhea had not improved. An abdominal CT scan showed acute pancreatitis and a hydropic gall bladder. Colon biopsies revealed focal acute colitis with atrophy and increased apoptosis in colonic crypts. EC MPS treatment was stopped for 4 days and the diarrhea ceased. Pregnancy An observational retrospective study of 20 males treated with MPA with 28 post-kidney transplant conceptions as compared with non-MPA treated males [117c]. No MPA dosage was specified. No significant differences were observed in the miscarriage rate between the 2 groups (6 in MPA-treated vs 2 in control). None of the children of the MPA-treated males had any physical malformations.

Thiopurines Thiopurines (mercaptopurine, thioguanine, and azathioprine) are approved by FDA for immunosuppression post-transplantation and during chemotherapy. Meta-analysis A meta-analysis of 13 studies of 149 198 patients with irritable bowel diseases treated with thiopurines (azathioprine and mercaptopurine) showed that these agents significantly increased overall skin cancer risk (risk ratio 1.8, 95% CI 1.14–2.87, P ¼ 0.013) [118M]. No specific dosage of therapy was reported. While thiopurines were not

associated with the development of melanoma, nonmelanoma cancers were associated with the use of these agents (risk ratio 1.88, 05% CI 1.48–2.38). Another meta-analysis of 18 studies on patients treated with mercaptopurine (50 mg/day) or azathioprine (2.0–2.5 mg/kg/day) for irritable bowel disease (IBD) showed a moderately increased risk of non-melanoma skin cancer (NMSC) with therapy duration-dependent manner [119R]. Seven of these studies reported a statistically significant hazard ratio ranging from 0.85 to 5.9, six of which were statistically significant. There were 6 studies that reported odd ratios ranging from 0.99 to 5.26, in which 5 were statistically significant. Incidence rate ratios were reported by 3 studies with a range from 1.46 to 2.9 with non-statistically significant 95% confident intervals. One study provided a proportional reporting ratio for NMSC (3.83, 95% CI 1.83–7.04) and one study reported standardized incidence ratios (3.88, 95% CI 1.04–9.93). The risk for NMSC was found to be reversible upon therapy discontinuation. Younger patients seemed to be at a greater risk. A meta-analysis of 14 studies in 219 Asian patients (Japanese, Chinese, Korean, Thai, and Indian) treated with azathioprine for various disease conditions showed that having NUDT15 R139C genotype (NUDT15 R139C, nucleoside diphosphate-linked moiety X-type motif 15 encoding p.Arg139Cys) significantly increased susceptibility to thiopurine-induced leukopenia [120M]. In particular, the NUDT15 c.415C > T allele increased the risk of developing leukopenia by threefolds. Azathioprine dose range was 0.5–1.5 mg/kg/day. Observational studies Another retrospective case–control study of 15 Japanese adults treated with azathioprine for dermatological diseases indicated that NUDT15 R139C homozygosity posed a higher risk of leukopenia and alopecia [121c]. These patients either were taking azathioprine or had taken azathioprine but stopped due to ADRs. Two patients with NUDT15 R139C homozygosity developed massive hair loss within 2 weeks of azathioprine initiation and agranulocytosis, and severe thrombocytopenia within 4 weeks of this therapy. A prospective study of 87 Chinese patients (79 females) treated with azathioprine 58.3 mg/day
19.17 for autoimmune diseases for at least 2 months showed that 27% patients heterozygous for NUDT15 R139C developed leukopenia and 1 homozygous patient had more severe leukopenia with severe hair loss [122c]. Overall, patients with the NUDT15 R139C allele had 84.4% sensitivity and 78.3% specificity for predicting leukopenia due to azathioprine treatment. The study also showed that the level of 6-thioguanosine triphosphate

IMMUNOSUPPRESSIVE DRUGS

(6-TGN), an azathioprine toxic metabolite, was not associated with the NUDT15 R139C or TPMT*3C genotypes. Another prospective study of 219 Chinese patients treated with azathioprine for irritable bowel diseases showed that the NUDT15 genotype was a better predictor for azathioprine-associated leukopenia than the TPMT genotype (TPMP, thiopurine methyltransferase) [123C]. A study of 182 Korean children with acute lymphoblastic leukemia (ALL) treated with thiopurines showed that the NUDT15 variants were associated with an increased risk of leukopenia in spite of the low 6-TGN levels [124C]. Patients with the NUDT15 variant had a reduced drug metabolism and were, therefore, given low-dose azathioprine. In spite of this alteration, these patients still experienced the longest duration of therapy interruption and leukopenia during the first year (P < 0.01) and had the lowest blood cell counts and the lowest levels of 6-TGN in this study. A cross-sectional study of 82 pediatric patients (aged 21 years and younger) who were treated with either azathioprine or mercaptopurine for Crohn’s disease investigated the association of thiopurines and alterations in anthropometric parameters [125c]. The study showed that these agents were significantly associated with delayed bone age indicated by the anthropometric parameters, such as lower mean triceps skinfold, subscapular skinfold, mid-arm circumference, weight, BMI, and Z-score. Other biomarkers were also collected including estimated sedimentation rate, C-reactive protein, and white blood cell count, and were found to be negatively associated with thiopurine therapies. A retrospective chart review of 290 patients with antineutrophil cytoplasmic antibody-associated (ANCA) vasculitis showed that those with azathioprine hypersensitivity had significantly lower TPMT activity [126C]. Clinical presentation of azathioprine hypersensitivity showed systemic inflammation as evidenced by fever, arthralgia, abdominal pain, nausea, elevated C-reactive protein level, and increased neutrophil counts. Azathioprine hypersensitivity syndrome might be associated with reduced TPMT activity and may occur even during concomitant prednisolone therapy. A retrospective cross-sectional study of 87 patients treated with azathioprine (mean dose 111 mg/kg/day) or 6-mercaptopurine (mean dose 60 mg/kg/day) for irritable bowel diseases showed that the 6-TGN levels were significantly higher in patients with no relapse as compared to those with relapse (P < 0.025) [127c]. Adjusted nadir 6-TGN levels 161 and median levels 264 were linked to fewer relapse episodes (HR 0.5, 95% 0.26–0.87, P ¼ 0.016; HR 0.4, 95% CI 0.2–0.82, P ¼ 0.14, respectively).

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Noncirrhotic portal hypertension (NCPH) A case report of 2 males (one 37-year-old and one 33-year-old) treated with combined allopurinol– mercaptopurine for complicated IBD for 4–5 years was both found to have NCPH and mild portal sclerosis from liver biopsy and splenomegaly from abdominal ultrasound [128A]. Increased levels of the end-metabolite, 6-TGN, contributed to nodular regenerative hyperplasia, an important cause of NCPH [129A]. It was suggested that the addition of allopurinol to thiopurine contributed to the higher 6-TGN level. A 76-year-old male was treated with azathioprine (dose not reported) for his ileocolic Crohn’s disease for 10 years [130r]. He was found to have hepatoportal sclerosis with nodular regenerative hyperplasia from liver biopsy, resulting in portal hypertension, grade 2 ascites, and small esophageal varices. Although the natural history of this condition was not well established, histological regression was observed with the withdrawal of the drug. A population-based observational study of 7130 New Zealanders who were treated with thiopurines for a variety of disease conditions, the majority being for Crohn’s disease and ulcerative colitis [131C]. The thiopurine metabolite levels were investigated in 1065 patients who withdrew from therapy due to intolerance. 15% of these patients developed preferential 6-methyl mercaptopurine (6-MMP) production. Out of these 15%, 29 patients had late-onset shunting with 6-MMP production (between 5 months and >10 years later). This indicates the need to monitor 6-MMP along with 6-TGN level over a long period of time. Neonatal lymphopenia A normal-sized baby born at 38 weeks of gestation was found to have severe lymphopenia on day 10 postpartum [132A]. The mother was treated with azathioprine 100 mg/day for Crohn’s disease throughout the pregnancy. Genotyping test showed that the mother had intermediate TPMT activity and the infant had very low or absent TPMT activity. 6-TGN was found in the baby without the presence of 6-MMP. The infant developed profound lymphopenia on day 10 after birth which continued through her first 3 months of life. At 1-month age, prophylactic treatment with trimethoprim– sulfamethoxazole 25 mg/kg three times weekly was started. At 3 months of age, the biological balance normalized and 6-TGN became undetectable. Pancytopenia A 65-year-old male treated with azathioprine for resistant psoriatic arthritis for 5 weeks developed nadir pancytopenia and herpes simplex virus oral ulcers despite

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having normal TPMT activity [133A]. His clinical presentation resolved after azathioprine withdrawal. A 38-year-old Caucasian female treated with azathioprine (no dosage reported) for a month presented with cutaneous necrotizing vasculitis on her lower legs and pancytopenia [134A]. She was treated with corticosteroid, methotrexate, and hydroxychloroquine, but her vasculitis did not improve. She was also found to have MOCOS c.362C > T genetic variant which is responsible for slower thiopurine metabolism and resulting in accumulation of serum 6-TGN. The authors suspected that the dysfunctional homozygous sequence variant in the MOCOS gene presented in this patient was responsible for her xanthinuria type II development. Azathioprine was discontinued and her condition gradually resolved.

Fingolimod Fingolimod is a prodrug whose active metabolite inhibits lymphocyte release from lymph nodes via modulating sphingosine 1-phosphate receptor. It was approved by the FDA for relapsing MS for patients aged 10 years and older in 2010 [135S]. Depression A systematic review of 48 clinical trials (28 observational studies, and 2 case reports) investigated the effect of disease-modifying therapies on adverse psychiatric illnesses in patients with MS [136M]. The diseasemodifying therapies included in this analysis were natalizumab, fingolimod, dimethyl fumarate, teriflunomide, and alemtuzumab. Depression was the most common adverse psychiatric event with a frequency of up to 24.7%. The analysis did not demonstrate an increased risk of adverse psychiatric events induced by diseasemodifying therapies. 18 of these studies showed that treatment with fingolimod, natalizumab, or dimethyl fumarate improved depressive symptoms among these patients. Further investigation is needed to determine whether the positive psychiatric effect is directly associated with the drug or indirectly as a result of the improvement of the diseases being treated. Observational studies A case–control study of patients with MS compared the rate of varicella zoster virus (VZV) infection between fingolimod therapy (n ¼ 210) and IFN-β (n ¼ 210) [137C]. No specific dosage of drug therapy was reported. There was a significantly higher frequency of VZV DNA detection in the fingolimod group (7.6% vs 0%, P ¼ 0). A retrospective study of 114 patients with RRMS was conducted to assess predictors of bradycardia after the first dose of 0.5 mg fingolimod [138c]. Data on hourly

monitoring during the 6-h post-dose period showed heart rate significantly decreased at each hour (P < 0.001) and reached nadir level 4 h post-dose. Additional factors including BMI, optic nerve involvement, baseline heart rate, and T-peak-T-end interval were independent predictors of a greater heart rate decrease. Baseline greater systolic and diastolic blood pressures were also associated with a greater reduction in blood pressure post-dose. Progressive multifocal leukoencephalopathy (PML) A cohort study of 100 921 patients with MS investigated the incidence of MS treatment-associated PML using the FDA Adverse Event Reporting System database [139C]. MS treatment agents included natalizumab, fingolimod, DMF, dalfampridine, rituximab, glatiramer, IFN-β. No specific dosage on these drugs was reported. The frequency of PML overall, and for each drug, was higher in Japan compared to the United States. The highest incidence of PML was observed with natalizumab, fingolimod, and DMF, and was lowest with rituximab. A retrospective review used Novartis safety database included 15 fingolimod-treated patients developing PML in the absence of a previous history of natalizumab therapy [140c]. Fingolimod was given at 0.5 mg daily. The result showed a low risk for fingolimod-associated PML without prior natalizumab history with an estimated risk of 0.069 per 1000 patients (95% CI 0.039–0.114) and estimated incidence rate of 3.12 per 100 000 patient-years (95% CI 1.75–5.15). A 34-year-old female with a long history of RRMS was treated with fingolimod [141A]. Fingolimod dosage was not reported. A month after fingolimod withdrawal due to lymphopenia, she developed PML with mild immune reconstitution syndrome in the presence of JCV meningitis. She was treated for JCV meningitis with methylprednisolone 1 g IV for 3 days and oral mefloquine 375 mg weekly for 6 months. Two months after the initiation of JCV meningitis treatment, her CSF-JCV became negative and the serum lymphocyte count was normalized. Her PML symptoms gradually improved. Predictor for lymphopenia A study on 30 patients with RRMS treated with 0.5 mg/day fingolimod was monitored for 24-h heart rates [142c]. The severity of lymphopenia seemed to be associated with the degree of fingolimod-induced bradycardia. CNS infections A 40-year-old female treated with fingolimod for 2 years for RRMS presented with generalized weakness, headache, anorexia, and visual and auditory hallucinations [143A]. She was found to have Cryptococcal meningitis which was treated with IV amphotericin

IMMUNOENHANCING DRUGS

B and flucytosine. Fingolimod therapy was switched to natalizumab. Her clinical presentation gradually improved over the course of 6 weeks on aggressive anti-fungal therapies. A 49-year-old female with a 25-year history of RRMS developed severe aseptic temporal lobe encephalitis after 3.5 years on a licensed dose of fingolimod [144A]. Although CSF cultures and viral PCR were all negative, she responded well to IV acyclovir and antibiotics (ceftriaxone, vancomycin, and ampicillin) therapies, which could mean an underlying secondary infection. Her clinical presentation (CSF analysis, Montreal Cognitive Assessment score) improved after 1 month of anti-microbial therapies. Although fingolimod was held during the patient’s hospitalization, the authors did not report whether chronic fingolimod therapy was resumed after discharge. A 44-year-old female with a history of MS was treated with fingolimod for 2 years [145A]. Fingolimod dosage was not reported. The patient presented with paresthesia, cramps in her lower extremities, fever, headache, and confusion for which she was eventually diagnosed with rhombencephalitis of Listeria monocytogenes, accompanied with hydrocephalus. She was treated with IV ampicillin in addition to ventricular shunt for drainage. After 21 days of therapy, her clinical and neurological presentations markedly improved. The authors did not state whether fingolimod therapy was continued throughout the antibiotic treatment and after hospital discharge. Lymphoproliferative disorder A 38-year-old male treated with RRMS developed dysarthria, vertigo, vomiting, and imbalance in the presence of peripheral lymphopenia ensuing 6 months after fingolimod initiation [146A]. No fingolimod dosage was reported. Brain biopsy showed dominant T cell dysregulation. Fingolimod treatment was stopped. The intracerebral tumor-like lesion responded to chemotherapy induction and autologous hematopoietic stem cell transplantation. At a 6-month follow-up, the patient’s MS remained clinically and radiologically stable and the tumor-like lesions shrunk. The authors did not report whether a new treatment for MS was initiated after fingolimod discontinuation. A 53-year-old female was diagnosed with RRMS and initially treated with glatiramer acetate 20 mg/day and subsequently with IFN-β [147A]. Due to clinical disease activity, her treatment was switched to fingolimod (no dosage reported). After 3 years of fingolimod therapy, the patient developed cutaneous lymphoproliferative disorder, compatible with mycosis fungoides. It was treated successfully with fingolimod withdrawal, electron beam radiation therapy, and surgical excision.

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Central serous chorioretinopathy A 34-year-old male developed central serous chorioretinopathy with blurry vision in his right eye after 18 months of fingolimod 0.5 mg/day treatment [148A]. His vision was restored 2 weeks after fingolimod withdrawal. Cutaneous anaplastic large cell lymphoma A 42-year-old Iranian female was diagnosed with RRMS and initially treated with IFN-β [149A]. Due to an MS relapse, the IFN-β therapy was switched to fingolimod (no dosage reported). After 2 years of fingolimod treatment, she developed a mass on the right shoulder blade which was confirmed as cutaneous anaplastic large cell lymphoma. The mass regressed without treatment 2 months after fingolimod cessation. A 69-year-old female with MS also developed cutaneous large B-cell lymphoma on her right posterior neck after 2 years of fingolimod therapy (no dosage reported) [150A]. 4 doses of rituximab were planned to treat this tumor. Human papilloma virus-associated warts A case series of 5 patients with a history of MS treated with fingolimod for 17–58 months described the development of chronic HPV-associated warts in the presence of prolonged lymphopenia [151A]. In 4 out of 5 patients, the warts did not respond to a combination of standard therapies until fingolimod treatment was discontinued or its dosage was reduced. One patient progressed to metastatic HPV-associated anal squamous cell carcinoma. Neonatal dextrocardia A 34-year-old Iranian female was treated with fingolimod 0.5 mg/day for a 10-year history of MS. Her first pregnancy resulted in spontaneous abortion at 8 weeks of gestation [152A]. Her second unplanned pregnancy resulted in an infant with confirmed dextrocardia via vaginal delivery. Fingolimod was stopped at 7 weeks of gestation of the second pregnancy and the patient did not receive any treatment for her MS for the remainder of her pregnancy. Her family history was non-contributory.

IMMUNOENHANCING DRUGS Levamisole Levamisole (Ergamisol®) is approved to treat parasitic infections in veterinary medicine. It is no longer available in the US for human use [153S]; however, it is currently available in Canada to treat colon cancer in humans. Levamisole has been known in recent years to be a component of adulterated cocaine and the cause of

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agranulocytosis among cocaine abusers worldwide. Due to its short half-life of approximately 5 h, it is often not detected in blood and urine upon the patient’s hospitalization [156A]. Antineutrophil cytoplasmic antibody (ANCA) autoimmune disorders A systemic review of 111 studies revealed that levamisole-induced vasculopathy was linked to the female gender, had predominantly skin involvement, was positive ANCA
APL, and was associated with leukopenia, vasculitis, or vascular thrombotic histological lesions [154M]. These presentations tended to resolve with disrupted levamisole exposure. A 9-year-old Arab male with a 4-year history of steroid-dependent nephrotic syndrome was treated with levamisole (no dosage reported) and started to develop cutaneous ANCA vasculitis on the ears and neck, mild anemia, and hepatosplenomegaly over the course of a year [155A]. His clinical presentation gradually improved after levamisole withdrawal. A 36-year-old male with a history of regular cocaine use (approximately twice weekly) developed painful, pruritic erythematous pretibial lesion after his last cocaine use 2 days prior to his symptom development [156A]. It was presumed that his lesion was induced by levamisole-contaminated cocaine, given the favorable response to discontinuation of cocaine use during his 3-day hospitalization. The lesion improved without treatment. A 47-year-old male presented with a febrile ulceronecrotic dermatosis which was subsequently diagnosed with febrile ulcero-necrotic Mucha-Habermann disease [157A]. These effects were suspected to be secondary to a prior intense use of levamisole–cocaine. The patient was initially treated with systemic steroid 1 mg/kg/ day with no improvement. IV immunoglobulin G 2 g/ kg/day was started in the hospital and continued twice monthly in an outpatient setting for a year. In addition to a complete cessation of cocaine use, the patient’s skin condition eventually resolved. A 35-year-old female reported a history of hepatitis C, bipolar disorder, and IV drug abuse, including cocaine [158A]. She developed painful necrotic lesions on her ears, neck, face, and upper extremities in addition to gastric pain. She reported her last use of cracked cocaine was 3 days prior to the lesion development. She was diagnosed with cutaneous ANCA vasculitis, esophageal erosion, and gastric submucosal hemorrhages. She was treated with oral prednisone and medication for pain. After 10 days of hospitalization and no illicit drug use, her clinical presentation resolved. With the currently published cases on the association of levamisole and skin lesion, the authors suspected that the patient’s cutaneous

ANCA vasculitis and hemorrhagic gastritis were associated with her cocaine use. Another 39-year-old female with a history of IV drug abuse, hepatitis C, and hypothyroidism also developed ANCA-positive leukocytoclastic vasculitis, presented as dry necrotic lesions shortly after smoking crack cocaine [159A]. The dry necrotic ulcers on her right hand resulted in the amputation of her fourth and fifth fingers. The authors concluded that her skin lesions was consistent with the diagnosis of levamisole-induced vasculitis. A 59-year-old male, who was a regular cocaine user, developed neutropenic fever and agranulocytosis and was treated appropriately [160A]. He resumed cocaine use post-discharge. Three weeks later, he was hospitalized with the same condition in addition to a bowel ischemia which required bowel resection. After thorough differential diagnoses, levamisole-cocaine-induced neutropenia was thought to be most appropriate as a diagnosis of exclusion. A 40-year-old Hispanic male with a history of cocaine abuse presented with acute focal necrotizing glomerulonephritis with crescentic features and mild immune type deposition [161A]. His acute kidney injury improved with cocaine abstinence, steroid, and chemotherapeutic agents. A 10-year-old girl with a history of relapsing steroid-sensitive nephrotic syndrome also had the same presentation after 2.5 years of levamisole treatment [162A]. A prospective cohort study followed 46 primary vasculitis patients for 5 years, 22 patients with cocaine–levamisole ANCA vasculopathy and 24 patients with primary ANCA vasculitis [163c]. Leukocytoclastic vasculitis was found in both groups, but in the cocaine– levamisole ANCA vasculopathy, the lesions were often retiform geographic necrosis in nature and were found to often affect superficial cartilage of the nose and ears. A similar percentage of patients in both groups developed acute arthritis which was resolved with treatments. However, 4 patients in the cocaine– levamisole ANCA vasculopathy developed chronic deforming seronegative polyarthritis, including cicatricial cutaneous and facial deformities, unlike the primary ANCA vasculitis group which did not have these developments. A retrospective observational study of 30 patients diagnosed with levamisole-adulterated cocaine-induced vasculitis or vasculopathy in Columbia showed that the most common skin involvement was ear necrosis with retiform purpura with grade 4 in severity and extension being the most frequently observed [164c]. Glomerulonephritis was the most common extracutaneous manifestations, followed by joint symptoms and fever. Two patients had diffuse alveolar hemorrhage but did not require intubation.

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Cognitive impairment A parallel, comparative, controlled study of 29 chronic cocaine users compared users with either high or low levamisole exposure [165c]. High levamisole exposure was defined as levamisole–cocaine ratio >25% and low exposure <25%. Users in both groups used cocaine as their primary illegal drug with an approximate amount of >0.5 g per month. Those users with higher levamisole exposure had significantly more impaired cognition (attention and working memory and lower global cognitive index). In addition, this group had reduced executive functions with reduced cortical thickness, especially in the middle frontal gyrus.

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