**9. Hazards of biologic therapy**

The development of recombinant technology represented the single biggest advance leading to humanized products with minimal or no contaminants in comparison to products purified from animal tissues. Nevertheless, the type of manufacturing process including choice of cell type, culture medium, and purification method can result in changes to the protein. Mono‐ clonal antibodies represent a major class of successful biologics. Toxicities associated with these agents include those associated with the binding of the complementary determining region (CDR) with the target biologic molecule. [117, 118] Most of the concerns about safety of biologic therapy are related to the use of biologic agents particularly TNFi in the treatment of rheumatoid arthritis.

#### **9.1. Infections**

Bacterial, mycobacterial and fungal infections might occur during biologic therapy especially with tumor necrosis factor inhibitors. Infections usually occur in first year of treatment, including life threatening serious infections and mostly caused by intracellular pathogens (tubercle bacillus, listeria, histoplasma, atypical mycobacteria, coccidioidomycosis and legionella). Infection risk with biologic therapy in patients with autoimmune diseases signif‐ icantly correlated to the dose of glucocorticoids given in such patients.

An analysis of Medicare beneficiaries enrolled in the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania, USA demonstrated that among almost 16,000 patients with rheumatoid arthritis over the age of 65 years old, treatment with TNF inhibitors didn't increase the risk of serious bacterial infections when compared with patients who had received treatment with methotrexate. Another review of three European registries suggested an increased risk of several types of infections among patients treated with TNF inhibitors, including tuberculosis. Therapy with biologic agents especially TNFi carries a potential risk for reactivation of latent TB, reactivation of dormant hepatitis B or C infection. [117-121]

Hepatosplenic T cell lymphomas (HSTCL): There are over 200 documented HSTCL cases in literature. This is a very rare, aggressive and often fatal malignancy that may be associated with IBD (25%), immunosuppression or immunosuppressive drugs. HSTCL primarily affects children and young adults (< 30 yrs) who are receiving azathioprine or 6-mercaptopurine treatment for Crohn's colitis. This lymphoma also has been reported in a few adults (over age

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Melanoma and non-melanoma skin cancer (NMSC): have been reported to occur more commonly among patients with RA, especially in those receiving TNF inhibitors (TNFi).

Solid tumors: Increased rates of other solid tumors have been observed among patients treated with TNFi for inflammatory diseases other than RA. Three RCTs have described more solid tumors among patients receiving TNFi in studies of: [1] infliximab in COPD; [2] etanercept in granulomatosis polyangiitis (formerly Wegener's granulomatosis); and [3] golimumab in severe asthma. The finding of greater numbers of solid tumors among TNFi-treated patients

Data from recent multiple registries and randomized controlled trials RCTs showed no increase in overall malignancy risk among RA patients treated with biologic agents (with the possible exception of an increased risk of melanoma recurrence with TNFi). Over 40,000 patients participating in numerous large databases and RA registries worldwide (CORRO‐ NA, National Databank for Rheumatic Diseases, ARTIS, BSRBR, BIOBADASER,LO‐ RHEN), have shown consistent cancer incidence rates (~1%), both among TNFi- and nonbiologic DMARD treated patients. The noticed increase in the risk of hematological cancers in patients with autoimmune diseases particularly among males over the age of 65 years old should be balanced against the increased risk of lymphoma in rheumatoid arthritis.

The risk of aggravation of heart failure has been a major concern with TNF inhibition therapy particularly in patients classified as class III-IV according to the American heart Association. An analysis of the cardiovascular risk in rheumatoid arthritis patients treated with TNF inhibitors demonstrated no difference in cardiovascular events when compared with patients treated with conventional disease-modifying anti-rheumatic drugs. Increase in the risk of

–Vasculitis: cases of TAK arteritis, ANCA associated vasculitis (Wegener's granulomatosis) and deep cutaneous vasculitis have been reported in rheumatoid arthritis patients treated with

in these relatively small RCTs was unexpected and remains of uncertain significance.

60 yrs.) receiving TNFi for RA. [122, 123]

[124, 125, 126](Table 3)

**9.3. Cardiac complications**

**9.4. Autoimmune phenomena**

–Drug induced lupus.

–Sarcoidosis.

dyslipidemia was observed with anti IL-6 therapy. [120]

tumor necrosis factor inhibitors. [47, 127-133].

–Human anti-chimeric antibodies with or without autoimmune phenomena.


**Table 4.** Standardized Incidence Ratios (SIR) for Lymphoma and Malignancies in RA on Biologics versus the Population Rate from Package Insert or Registration RCTs\* [126]

#### **9.2. Malignancy**

Lymphomas: Increased risk for lymphoma (with anti-TNF therapy). Concern regarding a potential relationship between use of biologic agents and lymphoma arose in 2003 when the FDA noted 6 lymphomas among the first 6303 RA patients treated with etanercept, infliximab and adalimumab, but none in the control subjects treated with placebo during the first six months of exposure. [122, 123]

Hepatosplenic T cell lymphomas (HSTCL): There are over 200 documented HSTCL cases in literature. This is a very rare, aggressive and often fatal malignancy that may be associated with IBD (25%), immunosuppression or immunosuppressive drugs. HSTCL primarily affects children and young adults (< 30 yrs) who are receiving azathioprine or 6-mercaptopurine treatment for Crohn's colitis. This lymphoma also has been reported in a few adults (over age 60 yrs.) receiving TNFi for RA. [122, 123]

Melanoma and non-melanoma skin cancer (NMSC): have been reported to occur more commonly among patients with RA, especially in those receiving TNF inhibitors (TNFi).

Solid tumors: Increased rates of other solid tumors have been observed among patients treated with TNFi for inflammatory diseases other than RA. Three RCTs have described more solid tumors among patients receiving TNFi in studies of: [1] infliximab in COPD; [2] etanercept in granulomatosis polyangiitis (formerly Wegener's granulomatosis); and [3] golimumab in severe asthma. The finding of greater numbers of solid tumors among TNFi-treated patients in these relatively small RCTs was unexpected and remains of uncertain significance.

Data from recent multiple registries and randomized controlled trials RCTs showed no increase in overall malignancy risk among RA patients treated with biologic agents (with the possible exception of an increased risk of melanoma recurrence with TNFi). Over 40,000 patients participating in numerous large databases and RA registries worldwide (CORRO‐ NA, National Databank for Rheumatic Diseases, ARTIS, BSRBR, BIOBADASER,LO‐ RHEN), have shown consistent cancer incidence rates (~1%), both among TNFi- and nonbiologic DMARD treated patients. The noticed increase in the risk of hematological cancers in patients with autoimmune diseases particularly among males over the age of 65 years old should be balanced against the increased risk of lymphoma in rheumatoid arthritis. [124, 125, 126](Table 3)

#### **9.3. Cardiac complications**

An analysis of Medicare beneficiaries enrolled in the Pharmaceutical Assistance Contract for the Elderly in Pennsylvania, USA demonstrated that among almost 16,000 patients with rheumatoid arthritis over the age of 65 years old, treatment with TNF inhibitors didn't increase the risk of serious bacterial infections when compared with patients who had received treatment with methotrexate. Another review of three European registries suggested an increased risk of several types of infections among patients treated with TNF inhibitors, including tuberculosis. Therapy with biologic agents especially TNFi carries a potential risk for reactivation of latent TB, reactivation of dormant hepatitis B or C

**Table 4.** Standardized Incidence Ratios (SIR) for Lymphoma and Malignancies in RA on Biologics versus the Population

Lymphomas: Increased risk for lymphoma (with anti-TNF therapy). Concern regarding a potential relationship between use of biologic agents and lymphoma arose in 2003 when the FDA noted 6 lymphomas among the first 6303 RA patients treated with etanercept, infliximab and adalimumab, but none in the control subjects treated with placebo during the first six

Rate from Package Insert or Registration RCTs\* [126]

months of exposure. [122, 123]

**9.2. Malignancy**

infection. [117-121]

262 Updates in the Diagnosis and Treatment of Vasculitis

The risk of aggravation of heart failure has been a major concern with TNF inhibition therapy particularly in patients classified as class III-IV according to the American heart Association. An analysis of the cardiovascular risk in rheumatoid arthritis patients treated with TNF inhibitors demonstrated no difference in cardiovascular events when compared with patients treated with conventional disease-modifying anti-rheumatic drugs. Increase in the risk of dyslipidemia was observed with anti IL-6 therapy. [120]

#### **9.4. Autoimmune phenomena**

–Drug induced lupus.

–Sarcoidosis.

–Human anti-chimeric antibodies with or without autoimmune phenomena.

–Vasculitis: cases of TAK arteritis, ANCA associated vasculitis (Wegener's granulomatosis) and deep cutaneous vasculitis have been reported in rheumatoid arthritis patients treated with tumor necrosis factor inhibitors. [47, 127-133].

Demyelinating diseases demyelinating neuropathies, and flare of multiple sclerosis and other diseases of the central nervous system have been reported with tumor necrosis factor inhibition therapy. [134]

[2] Chung, S. A, & Seo, P. Advances in the use of biologic agents for the treatment of

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[3] 3- Vassalli P. The pathophysiology of tumor necrosis factors. Annu. Rev. Immunol.

[4] Aries, P. M, Lamprecht, P, & Gross, W. L. Biological therapies: new treatment options for ANCA-associated vasculitis? Expert Opin. Biol. Ther. 7(4), 521-533 ((2007).

[5] Cush, J, & Kavanaugh, A. TNF-α blocking therapies, in Rheumatology. 4th ed. Hoch‐

[6] Shealy, D. Characterization of golimumab (CNTO 148), a novel monoclonal antibody

[7] Nesbitt, A, Fossati, G, Bergin, M, et al. Mechanism of action of certolizumab pegol (CDP870): in vitro comparison with other anti-tumor necrosis factor agents. Inflamm.

[8] Booth, A. D, Jefferson, H. J, Ayliffe, W, Andrews, P. A, & Jayne, D. R. Safety and effi‐ cacy of TNF α blockade in relapsing vasculitis. Ann. Rheum. Dis. 61, 559 ((2002).

[9] Josselin, L, Mahr, A, Cohen, P, et al. Infliximab efficacy and safety against refractory systemic necrotising vasculitides: long-term follow-up of 15 patients. Ann. Rheum.

[10] Bartolucci, P, Ramanoelina, J, Cohen, P, et al. Efficacy of the anti-TNF-α antibody in‐ fliximab against refractory systemic vasculitides: an open pilot study on 10 patients.

[12] Johnston, S. L, Lock, R. J, & Gompels, M. M. Takayasu arteritis: a review. J. Clin.

[13] Mason, J. C. Takayasu arteritis- advances in diagnosis and management. Nat. Rev.

[14] Kerr, G. S, Hallahan, C. W, Giordano, J, et al. Takayasu arteritis. Ann. Intern. Med.

[15] Rossa, A. D, Tavoni, A, Merlini, G, et al. Two Takayasu arteritis patients successfully treated with infliximab: a potential disease-modifying agent? Rheumatology (Ox‐

[16] Karageorgaki, Z. T, Mavragani, C. P, Papathanasiou, M. A, & Skopouli, F. N. Inflixi‐ mab in Takayasu arteritis: a safe alternative? Clin. Rheumatol. 26, 984-987 ((2007).

[17] Tanaka, F, Kawakami, A, Iwanaga, N, et al. Infliximab is effective for Takayasu arter‐ itis refractory to glucocorticoid and methotrexate. Intern. Med. 45, 313-316 ((2006).

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(1992),10, 411-452.

#### **9.5. Pulmonary complications**

Flare and progression of interstitial lung disease, allergic pneumonitis, new onset interstitial lung disease, culture-negative pneumonitis have been reported in cases treated with tumor necrosis factor inhibitors, tocilizumab, rituximab and golimumab. Flare of chronic obstructive pulmonary disease was reported in patients treated with abatacept. [135]

#### **9.6. Infusion reactions**

Biologics encompass a broad range of therapeutics that include proteins and other products derived from living systems. First dose reactions or infusion reactions are generally thought to be mediated via the Fc region of the antibody activating cytokine release, and have been observed with several antibodies. Usually, these effects (flu-like symptoms, etc.) are transient with subsequent dosing. Although biologics can have nonpharmacologic toxicities, these are less common than with small molecule drugs. Fever, shivering, chest pain, blood pressure oscillation, dyspnea, pruritus and/or urticaria, injection site reactions have been reproted. [118]

#### **9.7. Hematological complications: Neutropenias and thrombocytopenias**

The use of biologics as targeted therapies not only targets the currently identified pathogenic targets even more it might also improve the understanding of the pathophysiology of inflam‐ mation with autoimmunity. While the advent of biologics heralds a new era in the therapeutic armamentarium of the systemic vasculitis, evidences for their efficacy and safety in vasculitis is still in its infancy and are not yet superior to conventional immune-suppressants [136] with the exception of anti-CD20 B cell targeted therapy.
