The tumor necrosis factor (TNF) inhibitors infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) as well as the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara) are examples of the several biologic therapies that have been FDA approved for the treatment of psoriasis, psoriatic arthritis and other inflammatory diseases. Although generally safe and effective, several rare side effects have been documented in the literature in patients taking these medications. Indeed, an incidence rate of 53 cutaneous adverse events per 1,000 anti-TNF-alpha (TNF-α) patients has been recently reported.1 This article summarizes multiple categories of rare side effects of biologic therapy, including neurologic events, blood disorders, connective tissue disease and cardiac/metabolic abnormalities (Table).
Neurologic Events
Neurologic side effects have been reported with TNF-α inhibitors. Here, we discuss studies that have found demyelination and axonal polyneuropathy associated with TNF-α therapy.
Demyelination And Axonal Polyneuropathy
Demyelination has been documented following the therapeutic initiation of TNF-α inhibitors, particularly in association with rheumatologic diseases.2-5 Limb weakness, dysethesia, diploplia, numbness and sensory ataxia between 2 weeks and 14 months were the presenting signs and symptoms after the start of treatment. In some cases, patients presented with acute motor and sensory polyneuropathy as suggested by electrodiagnostic testing of nerve action potentials that improved with discontinuation of anti-TNF-α therapy and intravenous immunoglobulin (Ig) infusions.6-8 A recent article documented the case of a man treated for 6 months with infliximab for severe plaque psoriasis who was diagnosed with chronic inflammatory demyelinating polyneuropathy presenting as sudden onset weakness and numbness of his hands, which progressed to include global limb weakness and sensory ataxia.9 One review article found 151 reported cases of new-onset neurologic syndrome following anti-TNF-α therapy including central nervous system (CNS) involvement (64 cases), isolated optic neuritis (18 cases) and neuromuscular syndromes (69 cases).10 Another study searched the FDA’s Adverse Event Reporting System for reports of neurologic side effects during treatment with TNF-α inhibitors and found that the most common neurologic adverse events included peripheral neuropathy (38.3%) followed by CNS and/or spinal cord demyelination (19.8%).11
In contrast with TNF-α inhibitors, the IL-12/23 monoclonal antibody ustekinumab has not been associated with demyelinating neurologic events. Ustekinumab has previously been investigated as a possible therapy for demyelinating diseases such as multiple sclerosis. Although well-tolerated and not associated with exacerbations of demyelination, ustekinumab was not statistically different from placebo regarding effectiveness as a treatment for multiple sclerosis.12,13 By extension, ustekinumab is a rational choice for patients with a history demyelinating neurologic disease.
Blood Disorders
Side effects of biologic therapy include blood disorders. Here, we highlight 4 blood disorders that occurred with etanercept, adalimumab and ustekinumab.
Neutropenia
Neutropenia has been associated with anti-TNF-α therapy. One review of the literature found 111 reported cases of transient neutropenia in 15 articles in patients receiving TNF-α inhibitors for psoriasis and psoriatic arthritis, as well as other rheumatologic diseases.14 Another retrospective cohort study estimated the incidence of transient neutropenia as 18.8% of patients with rheumatologic conditions receiving the therapy.15 Of these patients, only 4 patients (6%) developed serious infections, including osteomyelitis, pneumonia, splenic abscess and sepsis of unclear origin with no related deaths reported. Another case series described the recurrence of mild to moderate neutropenia on re-challenge with etanercept in several rheumatoid arthritis (RA) patients; the patients then chose to remain on etanercept therapy and have their blood counts monitored regularly. 16 Notably, these patients with neutropenia experienced no increased rate of infection during re-challenge with etanercept. The mechanism of TNF-inhibitor-induced neutropenia remains purely speculative.14-16
Thrombocytopenia
There have been at least 19 cases of TNF-α inhibitor associated thrombocytopenia reported in the literature.14 A retrospective study of 93 psoriasis patients receiving anti-TNF-α therapy found 4 cases of thrombocytopenia as detected by platelet count which recovered in 3 out of the 4 patients after discontinuation of the drug.17 Associated events included gingival bleeding, ecchymoses, petechiae and purpura. Thrombocytopenia has occurred in patients with other underlying diseases as well, such as Crohn’s disease and RA, at least 1 of which experienced a recurrence upon re-challenge.18,19 As with neutropenia, multiple mechanisms have been posited to underlie thrombocytopenia associated with TNF-inhibitor therapy.18,20
Thrombotic Thrombocytopenic Purpura
There appear to be 2 reported cases of thrombotic thrombocytopenic purpura (TPP) caused by biologic therapy. The first was in a psoriasis patient taking the IL-12/23 monoclonal antibody ustekinumab, who developed TPP requiring several weeks of high dose plasma exchange treatment.20 The second was related to the anti-TNF-α monoclonal antibody adalimumab in a patient being treated for Crohn’s disease.21 The patient presented with microangiopathic hemolytic anemia, acute renal failure, thrombotic purpura on the arms and headache but improved after transfusion of fresh frozen plasma and packed red blood cells with no subsequent complications.
Blood Eosinophilia
TNF-α antagonists have been associated with cases of primary eosinophilia and worsening of existing eosinophilia. These cases include patients treated for psoriasis, RA and Crohn’s disease.14,22-24 Upper limits of recorded eosinophil levels included 1,020 eosinophils/mm3, 1,550 eosinophils/µL; 1,480 eosinophils/µL and 1,270 eosinophils/µL. Of note, the 2005 product summary for etanercept notes eosinophilia as a reported serious adverse event during controlled trials.25 It has been postulated that TNF antagonism might induce an immune deviation from the Th1 cytokine pattern of psoriasis to the Th2 phenotype, which can lead to eosinophilia and elevated IgE levels.22-24
Connective Tissue Disease
Cases of connective tissue disease have been reported following treatment with TNF-α inhibitors. Here, we will discuss autoimmune hepatitis (AIH), lupus and antiphospholipid syndrome (APS).
Autoimmune Hepatitis
Several cases of AIH have been reported following anti-TNF-α therapy. These cases are distinct from the reactivation of viral hepatitis. The cases of AIH have been documented in patients with psoriasis, psoriatic arthritis and Crohn’s disease treated with TNF-α inhibitors.26-28 However, some researchers argue that it may be difficult to differentiate between true AIH and drug-induced AIH in patients with other autoimmune diseases because underlying AIH may only present during immunosuppression with anti-TNF-α therapy.29 Importantly, it may be difficult to differentiate between underlying AIH, drug-induced AIH or drug-induced liver injury as the laboratory values may be similar in all 3 scenarios. Nevertheless, anti-TNF-α therapy may contribute to the development of AIH by triggering autoantibodies, including anti-nuclear antibodies (ANA) and anti-dsDNA.
Lupus
There have been several reported cases of drug-induced lupus erythematosus or lupus-like syndrome in patients receiving TNF-α antagonists.26,30-32 Infliximab is the most common offending agent and underlying conditions in these cases included psoriasis, RA and Crohn’s disease.33 Presentation included interface dermatitis with superficial perivascular lymphocytic infiltrate, increased interstitial dermal connective tissue mucin, photosensitivity, worsening of distal joint arthritis, mouth ulcers and increased ANA and anti-smooth muscle antibodies. In an analysis of the long-term safety of adalimumab for psoriasis, only 2 events of cutaneous lupus and 1 event of anti-dsDNA antibody were reported, representing an incidence rate of 0.06 events/100 patients years.34
Antiphospholipid Syndrome
Rarely, there have been cases reported of patients who developed APS following anti-TNF-α therapy. Presentation included ischemia of fingers and toes and bilateral ischemia of legs following thrombosis.35-36 One case demonstrated neurological involvement evidenced by abnormal neuropsychiatric testing consistent with CNS lupus; elevated antiphospholipid antibodies in serum and response to anticoagulation therapy suggested APS as the cause of the neurological symptoms.6 Additionally, cranial magnetic resonance imaging revealed white matter changes suggesting a microangiopathy. Laboratory tests revealed elevated titers of antiphospholipid antibodies in all 3 cases.
Cardiac/Metabolic Abnormalities
The relationship between biologic therapy and cardiovascular events and metabolic abnormalities has been cited in the literature. In this section, we focus on some of the study findings related to these adverse events.
Major Adverse Cardiovascular Events
There is controversy regarding a potential increased risk of major adverse cardiovascular events (MACE) among patients receiving biologic therapy, particularly IL-12/23 monoclonal antibodies. An initial meta-analysis did not find a statistically significant difference between placebo and either anti-TNF-α therapy or anti-IL-12/23 therapy, although the authors cited continuing concern about reported higher numerical rates of MACE in patients receiving IL-12/23 monoclonal antibodies in clinical trials.37 Using a different statistical method, another meta-analysis of the clinical trials for 2 different IL-12/23 monoclonal antibodies (briakinumab [ABT-874] and ustekinumab) for the treatment of psoriasis found both a numerical and statistically significant difference in the number of patients who experienced MACE, with an estimated incidence of 1% of the study population who received IL-12/23 inhibitors.38 Another study specifically of briakinumab showed a 5-fold increase in risk of MACE when patients had 2 or more cardiovascular risk factors.39
Worsening Of Congestive Heart Failure
Reports differ on the potential effects of anti-TNF-α therapy in patients with existing congestive heart failure (CHF). One placebo-controlled pilot study of infliximab found a statistically significant increase in worsening of CHF in patients receiving 10 mg/kg dosing of the drug, but not those receiving 5 mg/kg dosing.40 Other studies failed to find a statistically significant difference in worsening of CHF in patients receiving TNF-α inhibitors compared to placebo, but cite reported cases of heart failure exacerbations that improved after discontinuation of treatment.41-44 Interestingly, early studies suggested a potential therapeutic effect of TNF-α inhibitors on CHF.45 In particular, there has been controversy regarding the effect of TNF-α inhibitors on CHF in RA patients. One study assessing the risk of hospitalization for CHF in RA patients on disease-modifying anti-rheumatic drugs found that both TNF-α inhibitors and methotrexate exhibited a protective effect against hospitalization for CHF.46 However, large-scale clinical trials of etanercept for CHF were stopped due to lack of benefit.47 Another study found that the prevalence of heart failure is already increased among patients with RA and did not find an increase in CHF among patients receiving anti-TNF-α therapy.48 Other studies have found no statistically significant difference in CHF exacerbations between RA patients treated with anti-TNF-α therapy and controls.49,50 The relationship between anti-TNF-α therapy and CHF therefore remains difficult to establish.
Weight Gain And Body Composition Change
Two retrospective analyses of patients receiving TNF-α inhibitors for plaque psoriasis documented statistically significant increases in body weight and body mass index (BMI) compared to those treated with methotrexate.51,52 Weight gain ranged from 0.5 kg to 2.5 +/- 3.3 kg over a 6-month period. A later prospective study of this population found that in addition to weight gain, patients experienced body composition change including increase in both lean mass (2.9% +/- 3.4%) and fat mass (8.9% +/- 17.3%) after 6 months.53 A similar study comparing the TNF-α inhibitor infliximab with the IL-12/23 antibody ustekinumab failed to find a statistically significant increase in BMI among patients receiving ustekinumab, suggesting that this effect is limited to the anti-TNF-α class of drugs.54
Conclusion
The long-term experience with most biologic agents has allowed an extensive cataloging of rare adverse events over many years. However, these events that follow the administration of TNF inhibitors and ustekinumab remain rare. Biologics should be viewed as relatively safe and effective for the majority of patients for whom they are prescribed. Regardless, proper patient selection for treatment with these drugs is paramount, and, when occurring, rare adverse events should only be ascribed to the prescribed drug when all other possible etiologies have been ruled out. n
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
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2. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869.
3. Jarand J, Zochodne DW, Martin LO, Voll C. Neurological complications of infliximab. J Rheumatol. 2006;33(5):1018-1020.
4. Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology. 2005;64(5):1468-1470.
5. Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-alpha antagonists. Muscle Nerve. 2010;41(5):723-727.
6. Nozaki K, Silver RM, Stickler DE, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci. 2011;342(5):352-355.
7. Faivre A, Franques J, De Paula AM, et al. Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J Neurol Sci. 2010;291(1-2):103-106.
8. Tektonidou MG, Serelis J, Skopouli FN. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin Rheumatol. 2007;26(2):258-260.
9. Foulkes AC, Wheeler L, Gosal D, Griffiths CE, Warren RB. Development of CIDP in a patient receiving infliximab for psoriasis. Br J Dermatol. Published online ahead of print August 5, 2013.
10. Solomon AJ, Spain RI, Kruer MC, Bourdette D. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler. 2011;17(12):1472-1487.
11. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther. 2013;38(4):388-396.
12. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796-804.
13. Elliott M, Benson J, Blank M, et al. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci. 2009;1182:97-110.
14. Bessissow T, Renard M, Hoffman I, Vermeire S, Rutgeerts P, Van Assche G. Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy. Aliment Pharmacol Ther. 2012;36(4):312-323.
15. Hastings R, Ding T, Butt S, et al. Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). 2010;62(6):764-769.
16. Haroon M, Daly M, Harney S. Re-challenge with etanercept in patients with etanercept-induced neutropenia. Clin Rheumatol. 2012;31(1):151-155.
17. Brunasso AM, Massone C. Thrombocytopenia associated with the use of anti-tumor necrosis factor-alpha agents for psoriasis. J Am Acad Dermatol. 2009;60(5):781-785.
18. Casanova MJ, Chaparro M, Martínez S, Vicuña I, Gisbert JP. Severe adalimumab-induced thrombocytopenia in a patient with Crohn’s disease.
J Crohns Colitis. 2012;6(10):1034-1037.
19. Pathare SK, Heycock C, Hamilton J. TNF alpha blocker-induced thrombocytopenia. Rheumatology (Oxford). 2006;45(10):1313-1314.
20. Huang SH, Xenocostas A, Moist LM, Crowther M, Moore JC, Clark WF. Ustekinumab associated thrombotic thrombocytopenic purpura. Transfus Apher Sci. 2012;47(2):185-188.
21. Zbaras B, Sam LN, Grimm MC. Thrombotic thrombocytopenic purpura associated with adalimumab (Humira) treatment in Crohn disease. Intern Med J. 2013;43(2):216-217.
22. Cancelliere N, Barranco P, Vidaurrázaga C, Benito DM, Quirce S. Subacute prurigo and eosinophilia in a patient with rheumatoid arthritis receiving infliximab and etanercept. J Investig Allergol Clin Immunol. 2011;21(3):248-249.
23. Malisiewicz B, Murer C, Pachlopnik Schmid J, French LE, Schmid-Grendelmeier P, Navarini AA. Eosinophilia during psoriasis treatment with TNF antagonists. Dermatology. 2011;233(4):311-315.
24. Vester K, Rüger RD, Harth W, Simon JC. Transient blood eosinophilia during treatment with adalimumab. J Eur Acad Dermatol Venereol. 2012;26(7):924-925.
25. Wyeth summary of product characteristics Enbrel – 50 mg.https://www.enbrel.eu/Portals/10/Enbrel_50mg_SPC_pre-filled%20syringe.pdf. Accessed November 12, 2013.
26. Dang LJ, Lubel JS, Gunatheesan S, Hosking P, Su J. Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. Australas J Dermatol. Published online ahead of print May 8, 2013.
27. Germano V, Picchianti Diamanti A, Baccano G, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Theum Dis. 2005;64(10):1519-1520.
28. Cravo M, Silva R, Serrano M. Autoimmune hepatitis induced by infliximab in a patient with Crohn’s disease with no relapse after switching to adalimumab. BioDrugs. 2010;24(suppl 1):25-27.
29. Efe C. Drug induced autoimmune hepatitis and TNF-α blocking agents: is there a real relationship? Autoimmun Rev. 2013;12(3):337-339.
30. Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists.
J Cutan Pathol. 2012;39(5):481-492.
31. Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum. 2008;37(6):381-387.
32. Wilkerson E, Hazey MA, Bahrami S, Callen JP. Golimumab-exacerbated subacute cutaneous lupus erythematosus. Arch Dermatol. 2012;148(10):1186-1190.
33. Almoallim H, Al-Ghamdi Y, Almaghrabi H, Alyasi O. Anti-tumor necrosis factor-α induced systemic lupus erythematous. Open Rheumatol J. 2012;6:315-319.
34. Leonardi C, Papp K, Strober B, et al. The long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials. Am J Clin Dermatol. 2011;12(5):321-337.
35. Hemmati I, Kur J. Adalimumab-associated antiphospholipid syndrome: a case report and review of the literature. Clin Rheumatol. 2013;32(7):1095-1098.
36. Nosbaum A, Goujon C, Fleury B, Guillot I, Nicolas JF, Bérard F. Arterial thrombosis with anti-phospholipid antibodies induced by infliximab. Eur J Dermatol. 2007;17(6):546-547.
37. Ryan C, Leonardi C, Krueger J, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA. 2011;306(8):864-871.
38. Tzellos T, Kyrgidis A, Zouboulis CC. Re-evaluation of the risk for major adverse cardiovascular events in patients treated with anti-IL-12/23 biological agents for chronic plaque psoriasis: a meta-analysis of randomized controlled trials. J Eur Acad Dermatol Venereol. 2013;27(5):622-627.
39. Langley RG, Papp K, Gottlieb AB, et al. Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis. J Eur Acad Dermatol Venereol. 2013;27(10):1252-1261.
40. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133-3140.
41. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794.
42. Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807-811.
43. Stevenson ML, Lebwohl M. Iatrogenic effects of biologics for psoriasis. Clin Dermatol. 2011;29(6):614-621.
44. Castro Rocha FA, Silva FS. Reversible heart failure in a patient receiving etanercept for ankylosing spondylitis. J Clin Rheumatol. 2010;16(2):81-82.
45. Bozkurt B, Torre-Amione G, Warren MS, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure Circulation. 2001;103(8):1044-1047.
46. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford). 2005;44(5):677-680.
47. Louis A, Cleland JG, Crabbe S, et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail. 2001;3(3):381-387.
48. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med. 2004;116(5):305-311.
49. Cole J, Busti A, Kazi, S. The incidence of new onset congestive heart failure and heart failure exacerbation in Veteran’s Affairs patients receiving tumor necrosis factor alpha antagonists. Rheumatol Int. 2007;27(4):369-373.
50. Listing J, Strangfeld A, Kekow J, et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 2008;58(3):667-677.
51. Gisondi P, Cotena C, Tessari G, Girolomoni G. Anti-tumour necrosis factor-alpha therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study. J Eur Acad Dermatol Venereol. 2008;22(3):341-344.
52. Saraceno R, Schipani C, Mazzotta A, et al. Effect of anti-tumor necrosis factor-alpha therapies on body mass index in patients with psoriasis. Pharmacol Res. 2008;57(4):290-295.
53. Renzo LD, Saraceno R, Schipani C, et al. Prospective assessment of body weight and body composition changes in patients with psoriasis receiving anti-TNF-α treatment. Dermatol Ther. 2011;24(4):446-451.
54. Gisondi P, Conti A, Galdo G, Piaserico S, De Simone C, Girolomoni G. Ustekinumab does not increase body mass index in patients with chronic plaque psoriasis: a prospective cohort study. Br J Dermatol. 2013;168(5):1124-1127.
The tumor necrosis factor (TNF) inhibitors infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) as well as the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara) are examples of the several biologic therapies that have been FDA approved for the treatment of psoriasis, psoriatic arthritis and other inflammatory diseases. Although generally safe and effective, several rare side effects have been documented in the literature in patients taking these medications. Indeed, an incidence rate of 53 cutaneous adverse events per 1,000 anti-TNF-alpha (TNF-α) patients has been recently reported.1 This article summarizes multiple categories of rare side effects of biologic therapy, including neurologic events, blood disorders, connective tissue disease and cardiac/metabolic abnormalities (Table).
Neurologic Events
Neurologic side effects have been reported with TNF-α inhibitors. Here, we discuss studies that have found demyelination and axonal polyneuropathy associated with TNF-α therapy.
Demyelination And Axonal Polyneuropathy
Demyelination has been documented following the therapeutic initiation of TNF-α inhibitors, particularly in association with rheumatologic diseases.2-5 Limb weakness, dysethesia, diploplia, numbness and sensory ataxia between 2 weeks and 14 months were the presenting signs and symptoms after the start of treatment. In some cases, patients presented with acute motor and sensory polyneuropathy as suggested by electrodiagnostic testing of nerve action potentials that improved with discontinuation of anti-TNF-α therapy and intravenous immunoglobulin (Ig) infusions.6-8 A recent article documented the case of a man treated for 6 months with infliximab for severe plaque psoriasis who was diagnosed with chronic inflammatory demyelinating polyneuropathy presenting as sudden onset weakness and numbness of his hands, which progressed to include global limb weakness and sensory ataxia.9 One review article found 151 reported cases of new-onset neurologic syndrome following anti-TNF-α therapy including central nervous system (CNS) involvement (64 cases), isolated optic neuritis (18 cases) and neuromuscular syndromes (69 cases).10 Another study searched the FDA’s Adverse Event Reporting System for reports of neurologic side effects during treatment with TNF-α inhibitors and found that the most common neurologic adverse events included peripheral neuropathy (38.3%) followed by CNS and/or spinal cord demyelination (19.8%).11
In contrast with TNF-α inhibitors, the IL-12/23 monoclonal antibody ustekinumab has not been associated with demyelinating neurologic events. Ustekinumab has previously been investigated as a possible therapy for demyelinating diseases such as multiple sclerosis. Although well-tolerated and not associated with exacerbations of demyelination, ustekinumab was not statistically different from placebo regarding effectiveness as a treatment for multiple sclerosis.12,13 By extension, ustekinumab is a rational choice for patients with a history demyelinating neurologic disease.
Blood Disorders
Side effects of biologic therapy include blood disorders. Here, we highlight 4 blood disorders that occurred with etanercept, adalimumab and ustekinumab.
Neutropenia
Neutropenia has been associated with anti-TNF-α therapy. One review of the literature found 111 reported cases of transient neutropenia in 15 articles in patients receiving TNF-α inhibitors for psoriasis and psoriatic arthritis, as well as other rheumatologic diseases.14 Another retrospective cohort study estimated the incidence of transient neutropenia as 18.8% of patients with rheumatologic conditions receiving the therapy.15 Of these patients, only 4 patients (6%) developed serious infections, including osteomyelitis, pneumonia, splenic abscess and sepsis of unclear origin with no related deaths reported. Another case series described the recurrence of mild to moderate neutropenia on re-challenge with etanercept in several rheumatoid arthritis (RA) patients; the patients then chose to remain on etanercept therapy and have their blood counts monitored regularly. 16 Notably, these patients with neutropenia experienced no increased rate of infection during re-challenge with etanercept. The mechanism of TNF-inhibitor-induced neutropenia remains purely speculative.14-16
Thrombocytopenia
There have been at least 19 cases of TNF-α inhibitor associated thrombocytopenia reported in the literature.14 A retrospective study of 93 psoriasis patients receiving anti-TNF-α therapy found 4 cases of thrombocytopenia as detected by platelet count which recovered in 3 out of the 4 patients after discontinuation of the drug.17 Associated events included gingival bleeding, ecchymoses, petechiae and purpura. Thrombocytopenia has occurred in patients with other underlying diseases as well, such as Crohn’s disease and RA, at least 1 of which experienced a recurrence upon re-challenge.18,19 As with neutropenia, multiple mechanisms have been posited to underlie thrombocytopenia associated with TNF-inhibitor therapy.18,20
Thrombotic Thrombocytopenic Purpura
There appear to be 2 reported cases of thrombotic thrombocytopenic purpura (TPP) caused by biologic therapy. The first was in a psoriasis patient taking the IL-12/23 monoclonal antibody ustekinumab, who developed TPP requiring several weeks of high dose plasma exchange treatment.20 The second was related to the anti-TNF-α monoclonal antibody adalimumab in a patient being treated for Crohn’s disease.21 The patient presented with microangiopathic hemolytic anemia, acute renal failure, thrombotic purpura on the arms and headache but improved after transfusion of fresh frozen plasma and packed red blood cells with no subsequent complications.
Blood Eosinophilia
TNF-α antagonists have been associated with cases of primary eosinophilia and worsening of existing eosinophilia. These cases include patients treated for psoriasis, RA and Crohn’s disease.14,22-24 Upper limits of recorded eosinophil levels included 1,020 eosinophils/mm3, 1,550 eosinophils/µL; 1,480 eosinophils/µL and 1,270 eosinophils/µL. Of note, the 2005 product summary for etanercept notes eosinophilia as a reported serious adverse event during controlled trials.25 It has been postulated that TNF antagonism might induce an immune deviation from the Th1 cytokine pattern of psoriasis to the Th2 phenotype, which can lead to eosinophilia and elevated IgE levels.22-24
Connective Tissue Disease
Cases of connective tissue disease have been reported following treatment with TNF-α inhibitors. Here, we will discuss autoimmune hepatitis (AIH), lupus and antiphospholipid syndrome (APS).
Autoimmune Hepatitis
Several cases of AIH have been reported following anti-TNF-α therapy. These cases are distinct from the reactivation of viral hepatitis. The cases of AIH have been documented in patients with psoriasis, psoriatic arthritis and Crohn’s disease treated with TNF-α inhibitors.26-28 However, some researchers argue that it may be difficult to differentiate between true AIH and drug-induced AIH in patients with other autoimmune diseases because underlying AIH may only present during immunosuppression with anti-TNF-α therapy.29 Importantly, it may be difficult to differentiate between underlying AIH, drug-induced AIH or drug-induced liver injury as the laboratory values may be similar in all 3 scenarios. Nevertheless, anti-TNF-α therapy may contribute to the development of AIH by triggering autoantibodies, including anti-nuclear antibodies (ANA) and anti-dsDNA.
Lupus
There have been several reported cases of drug-induced lupus erythematosus or lupus-like syndrome in patients receiving TNF-α antagonists.26,30-32 Infliximab is the most common offending agent and underlying conditions in these cases included psoriasis, RA and Crohn’s disease.33 Presentation included interface dermatitis with superficial perivascular lymphocytic infiltrate, increased interstitial dermal connective tissue mucin, photosensitivity, worsening of distal joint arthritis, mouth ulcers and increased ANA and anti-smooth muscle antibodies. In an analysis of the long-term safety of adalimumab for psoriasis, only 2 events of cutaneous lupus and 1 event of anti-dsDNA antibody were reported, representing an incidence rate of 0.06 events/100 patients years.34
Antiphospholipid Syndrome
Rarely, there have been cases reported of patients who developed APS following anti-TNF-α therapy. Presentation included ischemia of fingers and toes and bilateral ischemia of legs following thrombosis.35-36 One case demonstrated neurological involvement evidenced by abnormal neuropsychiatric testing consistent with CNS lupus; elevated antiphospholipid antibodies in serum and response to anticoagulation therapy suggested APS as the cause of the neurological symptoms.6 Additionally, cranial magnetic resonance imaging revealed white matter changes suggesting a microangiopathy. Laboratory tests revealed elevated titers of antiphospholipid antibodies in all 3 cases.
Cardiac/Metabolic Abnormalities
The relationship between biologic therapy and cardiovascular events and metabolic abnormalities has been cited in the literature. In this section, we focus on some of the study findings related to these adverse events.
Major Adverse Cardiovascular Events
There is controversy regarding a potential increased risk of major adverse cardiovascular events (MACE) among patients receiving biologic therapy, particularly IL-12/23 monoclonal antibodies. An initial meta-analysis did not find a statistically significant difference between placebo and either anti-TNF-α therapy or anti-IL-12/23 therapy, although the authors cited continuing concern about reported higher numerical rates of MACE in patients receiving IL-12/23 monoclonal antibodies in clinical trials.37 Using a different statistical method, another meta-analysis of the clinical trials for 2 different IL-12/23 monoclonal antibodies (briakinumab [ABT-874] and ustekinumab) for the treatment of psoriasis found both a numerical and statistically significant difference in the number of patients who experienced MACE, with an estimated incidence of 1% of the study population who received IL-12/23 inhibitors.38 Another study specifically of briakinumab showed a 5-fold increase in risk of MACE when patients had 2 or more cardiovascular risk factors.39
Worsening Of Congestive Heart Failure
Reports differ on the potential effects of anti-TNF-α therapy in patients with existing congestive heart failure (CHF). One placebo-controlled pilot study of infliximab found a statistically significant increase in worsening of CHF in patients receiving 10 mg/kg dosing of the drug, but not those receiving 5 mg/kg dosing.40 Other studies failed to find a statistically significant difference in worsening of CHF in patients receiving TNF-α inhibitors compared to placebo, but cite reported cases of heart failure exacerbations that improved after discontinuation of treatment.41-44 Interestingly, early studies suggested a potential therapeutic effect of TNF-α inhibitors on CHF.45 In particular, there has been controversy regarding the effect of TNF-α inhibitors on CHF in RA patients. One study assessing the risk of hospitalization for CHF in RA patients on disease-modifying anti-rheumatic drugs found that both TNF-α inhibitors and methotrexate exhibited a protective effect against hospitalization for CHF.46 However, large-scale clinical trials of etanercept for CHF were stopped due to lack of benefit.47 Another study found that the prevalence of heart failure is already increased among patients with RA and did not find an increase in CHF among patients receiving anti-TNF-α therapy.48 Other studies have found no statistically significant difference in CHF exacerbations between RA patients treated with anti-TNF-α therapy and controls.49,50 The relationship between anti-TNF-α therapy and CHF therefore remains difficult to establish.
Weight Gain And Body Composition Change
Two retrospective analyses of patients receiving TNF-α inhibitors for plaque psoriasis documented statistically significant increases in body weight and body mass index (BMI) compared to those treated with methotrexate.51,52 Weight gain ranged from 0.5 kg to 2.5 +/- 3.3 kg over a 6-month period. A later prospective study of this population found that in addition to weight gain, patients experienced body composition change including increase in both lean mass (2.9% +/- 3.4%) and fat mass (8.9% +/- 17.3%) after 6 months.53 A similar study comparing the TNF-α inhibitor infliximab with the IL-12/23 antibody ustekinumab failed to find a statistically significant increase in BMI among patients receiving ustekinumab, suggesting that this effect is limited to the anti-TNF-α class of drugs.54
Conclusion
The long-term experience with most biologic agents has allowed an extensive cataloging of rare adverse events over many years. However, these events that follow the administration of TNF inhibitors and ustekinumab remain rare. Biologics should be viewed as relatively safe and effective for the majority of patients for whom they are prescribed. Regardless, proper patient selection for treatment with these drugs is paramount, and, when occurring, rare adverse events should only be ascribed to the prescribed drug when all other possible etiologies have been ruled out. n
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
1. Hernández MV, Sanmartí R, Cañete JD, et al. Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumour necrosis factor antagonists. Study based on the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases. Arthritis Care Res (Hoboken). Published online ahead of print August 7, 2013.
2. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869.
3. Jarand J, Zochodne DW, Martin LO, Voll C. Neurological complications of infliximab. J Rheumatol. 2006;33(5):1018-1020.
4. Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology. 2005;64(5):1468-1470.
5. Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-alpha antagonists. Muscle Nerve. 2010;41(5):723-727.
6. Nozaki K, Silver RM, Stickler DE, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci. 2011;342(5):352-355.
7. Faivre A, Franques J, De Paula AM, et al. Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J Neurol Sci. 2010;291(1-2):103-106.
8. Tektonidou MG, Serelis J, Skopouli FN. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin Rheumatol. 2007;26(2):258-260.
9. Foulkes AC, Wheeler L, Gosal D, Griffiths CE, Warren RB. Development of CIDP in a patient receiving infliximab for psoriasis. Br J Dermatol. Published online ahead of print August 5, 2013.
10. Solomon AJ, Spain RI, Kruer MC, Bourdette D. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler. 2011;17(12):1472-1487.
11. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther. 2013;38(4):388-396.
12. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796-804.
13. Elliott M, Benson J, Blank M, et al. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci. 2009;1182:97-110.
14. Bessissow T, Renard M, Hoffman I, Vermeire S, Rutgeerts P, Van Assche G. Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy. Aliment Pharmacol Ther. 2012;36(4):312-323.
15. Hastings R, Ding T, Butt S, et al. Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). 2010;62(6):764-769.
16. Haroon M, Daly M, Harney S. Re-challenge with etanercept in patients with etanercept-induced neutropenia. Clin Rheumatol. 2012;31(1):151-155.
17. Brunasso AM, Massone C. Thrombocytopenia associated with the use of anti-tumor necrosis factor-alpha agents for psoriasis. J Am Acad Dermatol. 2009;60(5):781-785.
18. Casanova MJ, Chaparro M, Martínez S, Vicuña I, Gisbert JP. Severe adalimumab-induced thrombocytopenia in a patient with Crohn’s disease.
J Crohns Colitis. 2012;6(10):1034-1037.
19. Pathare SK, Heycock C, Hamilton J. TNF alpha blocker-induced thrombocytopenia. Rheumatology (Oxford). 2006;45(10):1313-1314.
20. Huang SH, Xenocostas A, Moist LM, Crowther M, Moore JC, Clark WF. Ustekinumab associated thrombotic thrombocytopenic purpura. Transfus Apher Sci. 2012;47(2):185-188.
21. Zbaras B, Sam LN, Grimm MC. Thrombotic thrombocytopenic purpura associated with adalimumab (Humira) treatment in Crohn disease. Intern Med J. 2013;43(2):216-217.
22. Cancelliere N, Barranco P, Vidaurrázaga C, Benito DM, Quirce S. Subacute prurigo and eosinophilia in a patient with rheumatoid arthritis receiving infliximab and etanercept. J Investig Allergol Clin Immunol. 2011;21(3):248-249.
23. Malisiewicz B, Murer C, Pachlopnik Schmid J, French LE, Schmid-Grendelmeier P, Navarini AA. Eosinophilia during psoriasis treatment with TNF antagonists. Dermatology. 2011;233(4):311-315.
24. Vester K, Rüger RD, Harth W, Simon JC. Transient blood eosinophilia during treatment with adalimumab. J Eur Acad Dermatol Venereol. 2012;26(7):924-925.
25. Wyeth summary of product characteristics Enbrel – 50 mg.https://www.enbrel.eu/Portals/10/Enbrel_50mg_SPC_pre-filled%20syringe.pdf. Accessed November 12, 2013.
26. Dang LJ, Lubel JS, Gunatheesan S, Hosking P, Su J. Drug-induced lupus and autoimmune hepatitis secondary to infliximab for psoriasis. Australas J Dermatol. Published online ahead of print May 8, 2013.
27. Germano V, Picchianti Diamanti A, Baccano G, et al. Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis. Ann Theum Dis. 2005;64(10):1519-1520.
28. Cravo M, Silva R, Serrano M. Autoimmune hepatitis induced by infliximab in a patient with Crohn’s disease with no relapse after switching to adalimumab. BioDrugs. 2010;24(suppl 1):25-27.
29. Efe C. Drug induced autoimmune hepatitis and TNF-α blocking agents: is there a real relationship? Autoimmun Rev. 2013;12(3):337-339.
30. Hawryluk EB, Linskey KR, Duncan LM, Nazarian RM. Broad range of adverse cutaneous eruptions in patients on TNF-alpha antagonists.
J Cutan Pathol. 2012;39(5):481-492.
31. Costa MF, Said NR, Zimmermann B. Drug-induced lupus due to anti-tumor necrosis factor alpha agents. Semin Arthritis Rheum. 2008;37(6):381-387.
32. Wilkerson E, Hazey MA, Bahrami S, Callen JP. Golimumab-exacerbated subacute cutaneous lupus erythematosus. Arch Dermatol. 2012;148(10):1186-1190.
33. Almoallim H, Al-Ghamdi Y, Almaghrabi H, Alyasi O. Anti-tumor necrosis factor-α induced systemic lupus erythematous. Open Rheumatol J. 2012;6:315-319.
34. Leonardi C, Papp K, Strober B, et al. The long-term safety of adalimumab treatment in moderate to severe psoriasis: a comprehensive analysis of all adalimumab exposure in all clinical trials. Am J Clin Dermatol. 2011;12(5):321-337.
35. Hemmati I, Kur J. Adalimumab-associated antiphospholipid syndrome: a case report and review of the literature. Clin Rheumatol. 2013;32(7):1095-1098.
36. Nosbaum A, Goujon C, Fleury B, Guillot I, Nicolas JF, Bérard F. Arterial thrombosis with anti-phospholipid antibodies induced by infliximab. Eur J Dermatol. 2007;17(6):546-547.
37. Ryan C, Leonardi C, Krueger J, et al. Association between biologic therapies for chronic plaque psoriasis and cardiovascular events: a meta-analysis of randomized controlled trials. JAMA. 2011;306(8):864-871.
38. Tzellos T, Kyrgidis A, Zouboulis CC. Re-evaluation of the risk for major adverse cardiovascular events in patients treated with anti-IL-12/23 biological agents for chronic plaque psoriasis: a meta-analysis of randomized controlled trials. J Eur Acad Dermatol Venereol. 2013;27(5):622-627.
39. Langley RG, Papp K, Gottlieb AB, et al. Safety results from a pooled analysis of randomized, controlled phase II and III clinical trials and interim data from an open-label extension trial of the interleukin-12/23 monoclonal antibody, briakinumab, in moderate to severe psoriasis. J Eur Acad Dermatol Venereol. 2013;27(10):1252-1261.
40. Chung ES, Packer M, Lo KH, Fasanmade AA, Willerson JT. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation. 2003;107(25):3133-3140.
41. Singh JA, Wells GA, Christensen R, et al. Adverse effects of biologics: a network meta-analysis and Cochrane overview. Cochrane Database Syst Rev. 2011;(2):CD008794.
42. Kwon HJ, Coté TR, Cuffe MS, Kramer JM, Braun MM. Case reports of heart failure after therapy with a tumor necrosis factor antagonist. Ann Intern Med. 2003;138(10):807-811.
43. Stevenson ML, Lebwohl M. Iatrogenic effects of biologics for psoriasis. Clin Dermatol. 2011;29(6):614-621.
44. Castro Rocha FA, Silva FS. Reversible heart failure in a patient receiving etanercept for ankylosing spondylitis. J Clin Rheumatol. 2010;16(2):81-82.
45. Bozkurt B, Torre-Amione G, Warren MS, et al. Results of targeted anti-tumor necrosis factor therapy with etanercept (ENBREL) in patients with advanced heart failure Circulation. 2001;103(8):1044-1047.
46. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford). 2005;44(5):677-680.
47. Louis A, Cleland JG, Crabbe S, et al. Clinical Trials Update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the Scientific Sessions of the American College of Cardiology, 2001. Eur J Heart Fail. 2001;3(3):381-387.
48. Wolfe F, Michaud K. Heart failure in rheumatoid arthritis: rates, predictors, and the effect of anti-tumor necrosis factor therapy. Am J Med. 2004;116(5):305-311.
49. Cole J, Busti A, Kazi, S. The incidence of new onset congestive heart failure and heart failure exacerbation in Veteran’s Affairs patients receiving tumor necrosis factor alpha antagonists. Rheumatol Int. 2007;27(4):369-373.
50. Listing J, Strangfeld A, Kekow J, et al. Does tumor necrosis factor alpha inhibition promote or prevent heart failure in patients with rheumatoid arthritis? Arthritis Rheum. 2008;58(3):667-677.
51. Gisondi P, Cotena C, Tessari G, Girolomoni G. Anti-tumour necrosis factor-alpha therapy increases body weight in patients with chronic plaque psoriasis: a retrospective cohort study. J Eur Acad Dermatol Venereol. 2008;22(3):341-344.
52. Saraceno R, Schipani C, Mazzotta A, et al. Effect of anti-tumor necrosis factor-alpha therapies on body mass index in patients with psoriasis. Pharmacol Res. 2008;57(4):290-295.
53. Renzo LD, Saraceno R, Schipani C, et al. Prospective assessment of body weight and body composition changes in patients with psoriasis receiving anti-TNF-α treatment. Dermatol Ther. 2011;24(4):446-451.
54. Gisondi P, Conti A, Galdo G, Piaserico S, De Simone C, Girolomoni G. Ustekinumab does not increase body mass index in patients with chronic plaque psoriasis: a prospective cohort study. Br J Dermatol. 2013;168(5):1124-1127.
The tumor necrosis factor (TNF) inhibitors infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel), golimumab (Simponi) and certolizumab pegol (Cimzia) as well as the anti-interleukin (IL)-12/23 monoclonal antibody ustekinumab (Stelara) are examples of the several biologic therapies that have been FDA approved for the treatment of psoriasis, psoriatic arthritis and other inflammatory diseases. Although generally safe and effective, several rare side effects have been documented in the literature in patients taking these medications. Indeed, an incidence rate of 53 cutaneous adverse events per 1,000 anti-TNF-alpha (TNF-α) patients has been recently reported.1 This article summarizes multiple categories of rare side effects of biologic therapy, including neurologic events, blood disorders, connective tissue disease and cardiac/metabolic abnormalities (Table).
Neurologic Events
Neurologic side effects have been reported with TNF-α inhibitors. Here, we discuss studies that have found demyelination and axonal polyneuropathy associated with TNF-α therapy.
Demyelination And Axonal Polyneuropathy
Demyelination has been documented following the therapeutic initiation of TNF-α inhibitors, particularly in association with rheumatologic diseases.2-5 Limb weakness, dysethesia, diploplia, numbness and sensory ataxia between 2 weeks and 14 months were the presenting signs and symptoms after the start of treatment. In some cases, patients presented with acute motor and sensory polyneuropathy as suggested by electrodiagnostic testing of nerve action potentials that improved with discontinuation of anti-TNF-α therapy and intravenous immunoglobulin (Ig) infusions.6-8 A recent article documented the case of a man treated for 6 months with infliximab for severe plaque psoriasis who was diagnosed with chronic inflammatory demyelinating polyneuropathy presenting as sudden onset weakness and numbness of his hands, which progressed to include global limb weakness and sensory ataxia.9 One review article found 151 reported cases of new-onset neurologic syndrome following anti-TNF-α therapy including central nervous system (CNS) involvement (64 cases), isolated optic neuritis (18 cases) and neuromuscular syndromes (69 cases).10 Another study searched the FDA’s Adverse Event Reporting System for reports of neurologic side effects during treatment with TNF-α inhibitors and found that the most common neurologic adverse events included peripheral neuropathy (38.3%) followed by CNS and/or spinal cord demyelination (19.8%).11
In contrast with TNF-α inhibitors, the IL-12/23 monoclonal antibody ustekinumab has not been associated with demyelinating neurologic events. Ustekinumab has previously been investigated as a possible therapy for demyelinating diseases such as multiple sclerosis. Although well-tolerated and not associated with exacerbations of demyelination, ustekinumab was not statistically different from placebo regarding effectiveness as a treatment for multiple sclerosis.12,13 By extension, ustekinumab is a rational choice for patients with a history demyelinating neurologic disease.
Blood Disorders
Side effects of biologic therapy include blood disorders. Here, we highlight 4 blood disorders that occurred with etanercept, adalimumab and ustekinumab.
Neutropenia
Neutropenia has been associated with anti-TNF-α therapy. One review of the literature found 111 reported cases of transient neutropenia in 15 articles in patients receiving TNF-α inhibitors for psoriasis and psoriatic arthritis, as well as other rheumatologic diseases.14 Another retrospective cohort study estimated the incidence of transient neutropenia as 18.8% of patients with rheumatologic conditions receiving the therapy.15 Of these patients, only 4 patients (6%) developed serious infections, including osteomyelitis, pneumonia, splenic abscess and sepsis of unclear origin with no related deaths reported. Another case series described the recurrence of mild to moderate neutropenia on re-challenge with etanercept in several rheumatoid arthritis (RA) patients; the patients then chose to remain on etanercept therapy and have their blood counts monitored regularly. 16 Notably, these patients with neutropenia experienced no increased rate of infection during re-challenge with etanercept. The mechanism of TNF-inhibitor-induced neutropenia remains purely speculative.14-16
Thrombocytopenia
There have been at least 19 cases of TNF-α inhibitor associated thrombocytopenia reported in the literature.14 A retrospective study of 93 psoriasis patients receiving anti-TNF-α therapy found 4 cases of thrombocytopenia as detected by platelet count which recovered in 3 out of the 4 patients after discontinuation of the drug.17 Associated events included gingival bleeding, ecchymoses, petechiae and purpura. Thrombocytopenia has occurred in patients with other underlying diseases as well, such as Crohn’s disease and RA, at least 1 of which experienced a recurrence upon re-challenge.18,19 As with neutropenia, multiple mechanisms have been posited to underlie thrombocytopenia associated with TNF-inhibitor therapy.18,20
Thrombotic Thrombocytopenic Purpura
There appear to be 2 reported cases of thrombotic thrombocytopenic purpura (TPP) caused by biologic therapy. The first was in a psoriasis patient taking the IL-12/23 monoclonal antibody ustekinumab, who developed TPP requiring several weeks of high dose plasma exchange treatment.20 The second was related to the anti-TNF-α monoclonal antibody adalimumab in a patient being treated for Crohn’s disease.21 The patient presented with microangiopathic hemolytic anemia, acute renal failure, thrombotic purpura on the arms and headache but improved after transfusion of fresh frozen plasma and packed red blood cells with no subsequent complications.
Blood Eosinophilia
TNF-α antagonists have been associated with cases of primary eosinophilia and worsening of existing eosinophilia. These cases include patients treated for psoriasis, RA and Crohn’s disease.14,22-24 Upper limits of recorded eosinophil levels included 1,020 eosinophils/mm3, 1,550 eosinophils/µL; 1,480 eosinophils/µL and 1,270 eosinophils/µL. Of note, the 2005 product summary for etanercept notes eosinophilia as a reported serious adverse event during controlled trials.25 It has been postulated that TNF antagonism might induce an immune deviation from the Th1 cytokine pattern of psoriasis to the Th2 phenotype, which can lead to eosinophilia and elevated IgE levels.22-24
Connective Tissue Disease
Cases of connective tissue disease have been reported following treatment with TNF-α inhibitors. Here, we will discuss autoimmune hepatitis (AIH), lupus and antiphospholipid syndrome (APS).
Autoimmune Hepatitis
Several cases of AIH have been reported following anti-TNF-α therapy. These cases are distinct from the reactivation of viral hepatitis. The cases of AIH have been documented in patients with psoriasis, psoriatic arthritis and Crohn’s disease treated with TNF-α inhibitors.26-28 However, some researchers argue that it may be difficult to differentiate between true AIH and drug-induced AIH in patients with other autoimmune diseases because underlying AIH may only present during immunosuppression with anti-TNF-α therapy.29 Importantly, it may be difficult to differentiate between underlying AIH, drug-induced AIH or drug-induced liver injury as the laboratory values may be similar in all 3 scenarios. Nevertheless, anti-TNF-α therapy may contribute to the development of AIH by triggering autoantibodies, including anti-nuclear antibodies (ANA) and anti-dsDNA.
Lupus
There have been several reported cases of drug-induced lupus erythematosus or lupus-like syndrome in patients receiving TNF-α antagonists.26,30-32 Infliximab is the most common offending agent and underlying conditions in these cases included psoriasis, RA and Crohn’s disease.33 Presentation included interface dermatitis with superficial perivascular lymphocytic infiltrate, increased interstitial dermal connective tissue mucin, photosensitivity, worsening of distal joint arthritis, mouth ulcers and increased ANA and anti-smooth muscle antibodies. In an analysis of the long-term safety of adalimumab for psoriasis, only 2 events of cutaneous lupus and 1 event of anti-dsDNA antibody were reported, representing an incidence rate of 0.06 events/100 patients years.34
Antiphospholipid Syndrome
Rarely, there have been cases reported of patients who developed APS following anti-TNF-α therapy. Presentation included ischemia of fingers and toes and bilateral ischemia of legs following thrombosis.35-36 One case demonstrated neurological involvement evidenced by abnormal neuropsychiatric testing consistent with CNS lupus; elevated antiphospholipid antibodies in serum and response to anticoagulation therapy suggested APS as the cause of the neurological symptoms.6 Additionally, cranial magnetic resonance imaging revealed white matter changes suggesting a microangiopathy. Laboratory tests revealed elevated titers of antiphospholipid antibodies in all 3 cases.
Cardiac/Metabolic Abnormalities
The relationship between biologic therapy and cardiovascular events and metabolic abnormalities has been cited in the literature. In this section, we focus on some of the study findings related to these adverse events.
Major Adverse Cardiovascular Events
There is controversy regarding a potential increased risk of major adverse cardiovascular events (MACE) among patients receiving biologic therapy, particularly IL-12/23 monoclonal antibodies. An initial meta-analysis did not find a statistically significant difference between placebo and either anti-TNF-α therapy or anti-IL-12/23 therapy, although the authors cited continuing concern about reported higher numerical rates of MACE in patients receiving IL-12/23 monoclonal antibodies in clinical trials.37 Using a different statistical method, another meta-analysis of the clinical trials for 2 different IL-12/23 monoclonal antibodies (briakinumab [ABT-874] and ustekinumab) for the treatment of psoriasis found both a numerical and statistically significant difference in the number of patients who experienced MACE, with an estimated incidence of 1% of the study population who received IL-12/23 inhibitors.38 Another study specifically of briakinumab showed a 5-fold increase in risk of MACE when patients had 2 or more cardiovascular risk factors.39
Worsening Of Congestive Heart Failure
Reports differ on the potential effects of anti-TNF-α therapy in patients with existing congestive heart failure (CHF). One placebo-controlled pilot study of infliximab found a statistically significant increase in worsening of CHF in patients receiving 10 mg/kg dosing of the drug, but not those receiving 5 mg/kg dosing.40 Other studies failed to find a statistically significant difference in worsening of CHF in patients receiving TNF-α inhibitors compared to placebo, but cite reported cases of heart failure exacerbations that improved after discontinuation of treatment.41-44 Interestingly, early studies suggested a potential therapeutic effect of TNF-α inhibitors on CHF.45 In particular, there has been controversy regarding the effect of TNF-α inhibitors on CHF in RA patients. One study assessing the risk of hospitalization for CHF in RA patients on disease-modifying anti-rheumatic drugs found that both TNF-α inhibitors and methotrexate exhibited a protective effect against hospitalization for CHF.46 However, large-scale clinical trials of etanercept for CHF were stopped due to lack of benefit.47 Another study found that the prevalence of heart failure is already increased among patients with RA and did not find an increase in CHF among patients receiving anti-TNF-α therapy.48 Other studies have found no statistically significant difference in CHF exacerbations between RA patients treated with anti-TNF-α therapy and controls.49,50 The relationship between anti-TNF-α therapy and CHF therefore remains difficult to establish.
Weight Gain And Body Composition Change
Two retrospective analyses of patients receiving TNF-α inhibitors for plaque psoriasis documented statistically significant increases in body weight and body mass index (BMI) compared to those treated with methotrexate.51,52 Weight gain ranged from 0.5 kg to 2.5 +/- 3.3 kg over a 6-month period. A later prospective study of this population found that in addition to weight gain, patients experienced body composition change including increase in both lean mass (2.9% +/- 3.4%) and fat mass (8.9% +/- 17.3%) after 6 months.53 A similar study comparing the TNF-α inhibitor infliximab with the IL-12/23 antibody ustekinumab failed to find a statistically significant increase in BMI among patients receiving ustekinumab, suggesting that this effect is limited to the anti-TNF-α class of drugs.54
Conclusion
The long-term experience with most biologic agents has allowed an extensive cataloging of rare adverse events over many years. However, these events that follow the administration of TNF inhibitors and ustekinumab remain rare. Biologics should be viewed as relatively safe and effective for the majority of patients for whom they are prescribed. Regardless, proper patient selection for treatment with these drugs is paramount, and, when occurring, rare adverse events should only be ascribed to the prescribed drug when all other possible etiologies have been ruled out. n
Ms. Townsend is with The University of Connecticut Health Center in Farmington, CT.
Dr. Strober is with the department of dermatology at the University of Connecticut Health Center in Farmington, CT.
Disclosures: Dr. Strober is with the speakers bureau for AbbVie; consultant for AbbVie, Amgen, Celgene, Novartis, Merck, Lilly, Pfizer, Janssen and Maruho; investigator for AbbVie, Amgen, Novartis, Lilly and Janssen. Ms. Townsend has no conflicts of interest to report.
References
1. Hernández MV, Sanmartí R, Cañete JD, et al. Cutaneous adverse events during treatment of chronic inflammatory rheumatic conditions with tumour necrosis factor antagonists. Study based on the Spanish Registry of Adverse Events of Biological Therapies in Rheumatic Diseases. Arthritis Care Res (Hoboken). Published online ahead of print August 7, 2013.
2. Mohan N, Edwards ET, Cupps TR, et al. Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum. 2001;44(12):2862-2869.
3. Jarand J, Zochodne DW, Martin LO, Voll C. Neurological complications of infliximab. J Rheumatol. 2006;33(5):1018-1020.
4. Richez C, Blanco P, Lagueny A, Schaeverbeke T, Dehais J. Neuropathy resembling CIDP in patients receiving tumor necrosis factor-alpha blockers. Neurology. 2005;64(5):1468-1470.
5. Alshekhlee A, Basiri K, Miles JD, Ahmad SA, Katirji B. Chronic inflammatory demyelinating polyneuropathy associated with tumor necrosis factor-alpha antagonists. Muscle Nerve. 2010;41(5):723-727.
6. Nozaki K, Silver RM, Stickler DE, et al. Neurological deficits during treatment with tumor necrosis factor-alpha antagonists. Am J Med Sci. 2011;342(5):352-355.
7. Faivre A, Franques J, De Paula AM, et al. Acute motor and sensory axonal neuropathy and concomitant encephalopathy during tumor necrosis factor-alpha antagonist therapy. J Neurol Sci. 2010;291(1-2):103-106.
8. Tektonidou MG, Serelis J, Skopouli FN. Peripheral neuropathy in two patients with rheumatoid arthritis receiving infliximab treatment. Clin Rheumatol. 2007;26(2):258-260.
9. Foulkes AC, Wheeler L, Gosal D, Griffiths CE, Warren RB. Development of CIDP in a patient receiving infliximab for psoriasis. Br J Dermatol. Published online ahead of print August 5, 2013.
10. Solomon AJ, Spain RI, Kruer MC, Bourdette D. Inflammatory neurological disease in patients treated with tumor necrosis factor alpha inhibitors. Mult Scler. 2011;17(12):1472-1487.
11. Deepak P, Stobaugh DJ, Sherid M, Sifuentes H, Ehrenpreis ED. Neurological events with tumour necrosis factor alpha inhibitors reported to the Food and Drug Administration Adverse Event Reporting System. Aliment Pharmacol Ther. 2013;38(4):388-396.
12. Segal BM, Constantinescu CS, Raychaudhuri A, Kim L, Fidelus-Gort R, Kasper LH. Repeated subcutaneous injections of IL12/23 p40 neutralising antibody, ustekinumab, in patients with relapsing-remitting multiple sclerosis: a phase II, double-blind, placebo-controlled, randomised, dose-ranging study. Lancet Neurol. 2008;7(9):796-804.
13. Elliott M, Benson J, Blank M, et al. Ustekinumab: lessons learned from targeting interleukin-12/23p40 in immune-mediated diseases. Ann N Y Acad Sci. 2009;1182:97-110.
14. Bessissow T, Renard M, Hoffman I, Vermeire S, Rutgeerts P, Van Assche G. Review article: non-malignant haematological complications of anti-tumour necrosis factor alpha therapy. Aliment Pharmacol Ther. 2012;36(4):312-323.
15. Hastings R, Ding T, Butt S, et al. Neutropenia in patients receiving anti-tumor necrosis factor therapy. Arthritis Care Res (Hoboken). 2010;62(6):764-769.
16. Haroon M, Daly M, Harney S. Re-challenge with etanercept in patients with etanercept-induced neutropenia. Clin Rheumatol. 2012;31(1):151-155.
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