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 Table of Contents  
RHEUMATO-DERMATOLOGY SYMPOSIUM
Year : 2019  |  Volume : 3  |  Issue : 1  |  Page : 41-46

Biologicals in the management of rheumatodermatologic conditions and beyond


Department of Clinical Immunology and Rheumatology, Amrita Institute of Medical Sciences, Kochi, Kerala, India

Date of Web Publication14-Feb-2019

Correspondence Address:
C B Mithun
Amrita Institute of Medical Sciences, Kochi, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CDR.CDR_51_18

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  Abstract 


Biologicals are synthesized from living cells by biotechnology methods and typically include monoclonal antibodies and fusion proteins targeted against pathogenic cytokines, B or T cells, or its receptors. A biosimilar is a cheaper, manufactured product which is almost the same as biological. Appropriate patient selection is the key consideration before starting biologicals. Screening for tuberculosis is a must, except in case of rituximab. Tumor-necrosis-factor alpha inhibitors, interleukin (IL)-17A antagonists, anti-CD6 monoclonal antibodies (mAbs), and anti-IL-6 mAbs are discussed here for various indications.

Keywords: Autoimmune, biological, connective tissue disease, rheumatodermatological


How to cite this article:
Mithun C B, Harikrishnan B. Biologicals in the management of rheumatodermatologic conditions and beyond. Clin Dermatol Rev 2019;3:41-6

How to cite this URL:
Mithun C B, Harikrishnan B. Biologicals in the management of rheumatodermatologic conditions and beyond. Clin Dermatol Rev [serial online] 2019 [cited 2019 Jul 15];3:41-6. Available from: http://www.cdriadvlkn.org/text.asp?2019/3/1/41/252316




  Introduction Top


Inflammatory rheumatological diseases are chronic autoimmune multisystem diseases with skin involvement predominating in most.

Broad-spectrum immunosuppressants such as corticosteroids and synthetic disease-modifying anti rheumatoid drugs (sDMARDs) were conventionally used in the treatment of these conditions empirically, without understanding the exact pathogenesis of the disease and the therapeutic targets. Apart from adverse effects due to broad-spectrum immunosuppression, a significant proportion of these patients may not respond adequately to the treatment with these agents. The recent past has witnessed an explosion of our understanding of the pathophysiology of these diseases and the molecular pathways involved. This led to the development of new drugs, directly targeting molecules thought to be involved in the inflammatory process. The major breakthrough in the targeted therapy was the advent of biologicals, which are therapeutic agents made by recombinant DNA techniques, directed against the pro-inflammatory cytokines and cellular targets involved in the disease pathogenesis.

This is a review of biologicals and its role in the management of rheumatological conditions with dermatological manifestations, with a special emphasis on those drugs available in India. Drugs which are not marketed in India (ustekinumab, belimumab, ixekizumab, etc.) and indications of biologicals in diseases other than rheumatodermatological disorders are not purveyed here.


  Biologicals and Biosimilars Top


Biologicals are synthesized from living cells by biotechnology methods and typically include monoclonal antibodies (mAbs) and fusion proteins targeted against pathogenic cytokines, B- or T-cells, or its receptors. A biosimilar is a copy of the original biological product and is defined as “a biological product highly similar to the reference product not withstanding minor differences in clinically inactive components and has no clinically meaningful differences from the reference product in terms of safety, purity, and potency of the product.”[1] Although biosimilars are much cheaper when compared to innovator biologicals, the lack of long-term data on immunogenicity, efficacy, and safety is a major concern.


  Preliminary Concerns and Workup Top


Before starting any biological agent, patient selection is the key. Important factors considered while selecting patients are:

  1. Whether the disease is active as per disease activity assessment parameters of that particular disease
  2. Refractoriness of the disease to conventional therapy
  3. Affordability of the patient.


The decision to start a biological should be a shared decision between a patient and a treating clinician. The patient needs to be fully explained about the expected therapeutic goals, duration of biological therapy, and possible complications of the treatment. Complete hemogram, renal function tests, urine analysis, liver function tests, chest X-ray, screening for viral infections such as hepatitis B and C and HIV 1 and 2, electrocardiogram, and echocardiography (in selected cases) are done before starting any biological therapy. Detailed history-taking and clinical examination should be done to rule out any recent or active infection.[2]

Biologicals such as tumor-necrosis-factor alpha (TNF-α) inhibitors (TNFis) can predispose patients to tuberculosis (TB) and can reactivate TB in those patients with latent TB. Risk of TB infection/reactivation is a major concern in a TB-endemic country like India. Hence, a screening for latent TB with Mantoux test or interferon-gamma release assay should be done in all patients before treatment with TNFi.[3] Although the risk for TB reactivation is less with biologicals such as secukinumab and tocilizumab (TCZ), screening for latent TB is recommended before starting these drugs. Latent TB, if diagnosed, should be treated before starting the biological. Of note, there is no evidence for increased risk of TB with rituximab (RTX), and therefore, latent TB screening is not mandatory before starting RTX.[4]

It is essential to vaccinate all patients who are subjected to biological therapy unless contraindicated. Inactivated vaccines such as pneumococcal and influenza vaccines should be given to patients as it can reduce the risk of infection substantially. Live vaccines (BCG, yellow fever, herpes zoster, and oral polio) should be avoided during biological therapy. These should be given at least 4 weeks before starting biological therapy. If live vaccines are required while the patient is on therapy, then the biological has to be discontinued for at least three half-lives of that particular biological.[2]

The commonly used biologicals in India are shown in [Table 1].
Table 1: The commonly used biological agents available in India

Click here to view



  Tumor-Necrosis-Factor Alpha Inhibitors Top


TNF-α is a pro-inflammatory cytokine that plays a prominent role in the pathogenesis of many dermatologic and rheumatologic conditions such as psoriasis and psoriatic arthritis (PsA), rheumatoid arthritis (RA), inflammatory bowel disease (IBD), sarcoidosis, and Behcet's disease (BD). Currently, there are five biological therapies that target TNF: *infliximab, a chimeric human-murine mAb; *adalimumab and *golimumab, fully human anti-TNF-α mAb (IgG1); *etanercept, a fusion protein composed of a dimer of the extracellular portions of human TNFR2 (p75) fused to the Fc domain of human IgG1; and *certolizumab, a pegylated, humanized Fab fragment of an anti-TNF-α mAb.

Although the innovator adalimumab is not marketed in India, three biosimilars of adalimumab are available in India at present. Both the innovator and biosimilar of infliximab and etanercept are available in India, whereas there is no biosimilar for golimumab yet. Certolizumab pegol is still unavailable in India.

Indications

Psoriasis and psoriatic arthritis

Introduction of TNFis has revolutionized the treatment of psoriasis which was once considered a difficult to treat disease. All the five TNFis have demonstrated their efficacy in psoriasis and PsA. However, golimumab is not yet food and drug administration (FDA) approved for use in plaque psoriasis. Although comparative clinical trials have not been performed, all the TNFis are considered equally effective for PsA. Etanercept seems to have a slow onset of action and probably less effective when compared to other TNFis for cutaneous lesions of psoriasis.[5]

Behcet's disease

BD is a primary systemic vasculitis characterized by oral and genital ulcers along with cutaneous, ophthalmic, rheumatologic, neurologic, arterial, or venous system involvement. TNFis are recommended in severe and/or refractory cases of BD. Among TNFis, infliximab and adalimumab have the maximum evidence for use in BD.[6]

Hidradenitis suppurativa

Hidradenitis suppurativa (HS) is a chronic inflammatory skin condition affecting apocrine sweat glands characterized by clusters of painful boils or abscesses and fistulating sinuses with foul-smelling discharge. Joint symptoms typical of spondyloarthritis are well described in patients with HS. Adalimumab is the first biological therapy approved by FDA for this “difficult-to-treat” condition.[7] There is some evidence that TNFis with a similar mechanism of action, such as infliximab and golimumab, can be also effective in HS though not FDA approved.[8],[9] However, etanercept, which is considered as a weaker TNFi because of its unique mechanism of action, is found to be ineffective in HS.[10]

Sarcoidosis

TNFis are used as the third-line therapy in cases of sarcoidosis refractory to treatment with corticosteroids ( first-line therapy) and “disease-modifying antisarcoid drugs” (second-line therapy) such as methotrexate, azathioprine, leflunomide, hydroxychloroquine, mycophenolate, and cyclosporine. Infliximab and adalimumab are the preferred TNFis in sarcoidosis as they are the molecules with maximum experience and evidence in sarcoidosis.[11],[12] However, the use of TNFis for refractory skin lesions of sarcoidosis is controversial as the studies show conflicting results.[11],[13] Additional studies are needed to recommend TNFis, specifically for cutaneous sarcoidosis.

Rheumatoid arthritis vasculitis

Although TNFis are the first-line biologicals in refractory cases of RA, these are less studied in RA vasculitic ulcers refractory to conventional treatment with corticosteroids and sDMARDs. With the limited available evidence, TNFis are shown to be effective in nonhealing RA vasculitic ulcers.[14]

Pyoderma gangrenosum

Pyoderma gangrenosum (PG), a rare but serious cutaneous ulcerative condition, is well known to be associated with autoimmune diseases such as IBD and RA. TNFis have been tried successfully in refractory cases of PD.[15]

Reiter's disease

Here, nonsteroidal anti-inflammatory drugs, selective COX-2 inhibitors, and older DMARDs are the first- and second-line treatments of option, though adalimumab, infliximab, etanercept, and golimumab have been tried in refractory spondylitic cases. Of these, there is placebo-controlled study validation only for etanercept.[16]

Adverse effects

Injection site reactions, pruritus, and upper respiratory tract infections are the most common side effects of TNFis. The most significant and feared adverse effect of TNFis is TB infection, either reactivation of latent TB or a newly acquired tuberculous infection. Among the TNFis, etanercept has the least risk for TB reactivation. Severe, but uncommon side effects of TNFis include severe fungal infections, new onset or exacerbation of central nervous system demyelinating disorders, the possible increased risk of lymphoma, drug-induced lupus, and exacerbation of heart failure.


  Interleukin 17a Antagonists Top


Interleukin (IL)-17A cytokine has an important role in the pathogenesis of psoriasis and spondyloarthritis. Secukinumab, ixekizumab, and brodalumab are the IL-17A antagonists available at present. Secukinumab, a fully human monoclonal anti-IL-17A antibody, and ixekizumab, a humanized mAb against IL-17A, directly bind to IL-17A and inhibit its action, whereas brodalumab is an IL-17A receptor antagonist. Ixekizumab and brodalumab are not marketed in India yet.

Indications

Psoriasis and psoriatic arthritis

Both secukinumab and ixekizumab are approved for the use in psoriasis and PsA. At present, brodalumab is approved for use in refractory plaque psoriasis only. In comparative studies, secukinumab is found to be more effective than etanercept (FIXTURE study) and ustekinumab (CLEAR study) in clearing the psoriatic lesions and improving the patients' quality of life.[17],[18] No head-to-head trials of secukinumab with other biologicals in PsA are not available till now. Hence, the most national/international guidelines presently recommend TNFis as the first-line biological in PsA because of the long-term experience and the well-established risk–benefit profile of TNFis in PsA.

Adverse effects

The most common adverse effects of secukinumab include nasopharyngitis, diarrhea, upper respiratory tract infection, and increased risk of superficial candidal infection. Increased suicidal ideation has been noted with brodalumab. IL-17A antagonists should be used with caution in patients with IBD as cases of IBD were observed in the trials of IL-17A antagonists.

The risk of TB with IL-17A antagonists is minimal when compared to TNFis, which gives it an edge over TNFis, especially in a TB-endemic country like India.


  Itolizumab Top


Itolizumab is a humanized anti-CD6 mAb developed in India (Alzumab, Biocon Limited, Bangalore, India) and it selectively binds to CD6, which is a pan-T-cell marker and causes downregulation of T-cells, leading to a reduction in the synthesis of pro-inflammatory cytokines and chemokines.[19]

Indication

Psoriasis

Itolizumab is approved only in India and Cuba for the treatment of moderate-to-severe plaque psoriasis. However, response rate was lower than those reported in phase III trials of infliximab, adalimumab, and ustekinumab therapy.[19]

Adverse effects

The common adverse effects of itolizumab include infusion reactions, infections, and rarely exfoliative dermatitis, adjustment disorder with anxiety, erythrodermic psoriasis, and bacterial arthritis.


  Rituximab Top


Studies have shown that B-cells play a crucial role in autoimmunity and disease expression through autoantibody production, cytokine secretion, antigen presentation, and costimulatory effects. Thus, therapies targeting B-cells are an attractive option for treating connective tissue disorders. RTX is a chimeric mAb targeting CD20 antigen, located exclusively over the pre-B-lymphocytes and mature B-lymphocytes. RTX initially got approved for use in B-cell lymphoma followed by in refractory RA. Apart from these indications, RTX is widely tried in many refractory autoimmune rheumatological and dermatological conditions, mainly as off-label use.

Indications

Antineutrophil cytoplasmic antibody-associated vasculitis

Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) can present to a dermatologist with features of cutaneous small vessel vasculitis. Although not advised for mild manifestations of AAV, RTX along with high-dose steroids is recommended for inducing remission in new-onset organ-threatening or life-threatening AAV.[20] RTX is also used for remission maintenance of AAV (500 mg RTX infusions administered every 6 months) and is found to be better than azathioprine.[21]

Dermatomyositis

The largest randomized controlled trial (RCT) of RTX in dermatomyositis (DM) (the RIM-RTX for inflammatory myopathy trial) has failed to meet its primary and secondary endpoints. Even though the trial is considered as a failure, the majority of the patients (83%) had improvement in disease activity as per study definitions.[22] The experts propose that the faulty trial design may be the reason for the failure to meet the study objectives. Hence, although the evidence from RCT lacks for RTX in the treatment of DM, RTX is widely used in the treatment of refractory DM with varying success, especially for extracutaneous manifestations. However, studies of RTX in refractory cutaneous manifestations of DM have yielded conflicting results. Of note, a validated skin index for DM was not used in the RIM trial. Considering these facts, there is little evidence to recommend the use of RTX specifically for cutaneous DM.

Systemic lupus erythematosus

Even though the RCTs of RTX in systemic lupus erythematosus (SLE), EXPLORER and LUNAR trial, did not show any significant benefit compared with controls, RTX is continued to be considered as a treatment option for refractory SLE.[23],[24] This is mainly based on the evidence from case reports and observational studies. Studies of RTX in refractory cutaneous lesions of SLE has shown good efficacy in acute and subacute cutaneous lupus erythematosus, but unsatisfactory results in chronic cutaneous lupus erythematosus.[25]

Systemic sclerosis

The treatment of systemic sclerosis (SSc) is challenging as there is no proven disease-modifying therapy available for it until now. The evidence of benefit for RTX in SSc mainly comes from case series and uncontrolled observational studies. An observational case–control cohort study, largest study till date to assess the effects of RTX on the skin and lung fibrosis in systemic sclerosis, demonstrated a significant improvement in the modified Rodnan skin score and prevention of worsening lung fibrosis.[26] However, using RTX only for skin fibrosis is debatable as it is well known that skin tightening in SSc is self-limiting and self-resolving. The evidence is scarce for the efficacy of RTX in other manifestations of SSc. Hence, RTX may be considered as a treatment option in refractory cases of SSc with extensive skin involvement, especially when associated with lung fibrosis.

Rheumatoid arthritis vasculitic ulcers

Although RTX is a proven therapy for refractory RA, it is not formally evaluated in RA vasculitic ulcers. Evidence from case reports and case series suggest that RTX may a therapeutic option in treatment-refractory RA vasculitic ulcers.[27]

Adverse effects

The most common adverse effects of RTX are infusion reactions such as headache, nausea, and rigors, which are usually mild to moderate. Severe anaphylaxis causing death is also reported. Pretreatment with methylprednisolone (100 mg intravenous), acetaminophen, and antihistamine are recommended to reduce the incidence and severity of reactions. Infectious adverse events, largely upper respiratory tract infections, are also common. Rare, but more serious adverse reactions include severe bacterial infections, progressive multifocal leukoencephalopathy, nonmelanotic skin carcinoma, herpes zoster infection, hepatitis B reactivation, immune-mediated demyelination, and cytopenias.


  Tocilizumab Top


TCZ is a recombinant-humanized IL-6 receptor mAb and blocks the action of inflammatory cytokine IL-6. IL-6 plays an important role in the pathogenesis of inflammatory diseases such as RA and also in predominantly fibrotic diseases such as SSc. TCZ is already approved for use in RA, systemic-onset juvenile idiopathic arthritis (SOJIA), polyarticular juvenile idiopathic arthritis, and giant cell arteritis.

Indications

Adult-onset Still's disease

Adult-onset Still's disease (AOSD), the adult variant of SOJIA, usually presents with fever, evanescent skin rash, and arthritis. Although no RCTs evaluating the efficacy of TCZ in AOSD are available, TCZ is routinely used in the treatment of refractory AOSD mainly based on the promising results from meta-analysis, retrospective case series, and case reports.[28]

Systemic sclerosis

Results from a double-blind phase II trial of TCZ in SSc were encouraging (although not statistically significant) and the patients treated with TCZ showed an improvement trend in skin thickening and lung function when compared to the controls.[29] A phase III trial of TCZ in SSc is underway, and its results may give us a better idea about the status of TCZ in the management of SSc.

Adverse effects

Common adverse reactions of TCZ are injection site reactions, upper respiratory tract infections, nasopharyngitis, headache, and mucosal ulceration. Infusion reactions, increased liver enzymes, hypercholesterolemia, hypertension, and neutropenia are also seen.


  Conclusion Top


The introduction of biologicals has definitely improved the care of patients with refractory autoimmune rheumatological and dermatological conditions. However, no therapeutic agents come without its drawbacks which are true in biologicals also. The cost of therapy and infections are the main concerns for its use. Moreover, due to the rarity of diseases, evidence from RCTs is not available for many of these conditions. Hence a risk–benefit ratio needs to be assessed individually before starting a biological therapy. As we continue to improve our understanding of the immunologic basis of these diseases, newer and more efficient drugs, overcoming the shortcomings of currently available ones, are likely to be developed in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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U.S. Food and Drug Administration. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product-Draft Guidance. U.S. Food and Drug Administration; 2012. Available from: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. [Last accessed on 2018 Aug 21].  Back to cited text no. 1
    
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Holroyd CR, Seth R, Bukhari M, Malaviya A, Holmes C, Curtis E, et al. The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis-executive summary. Rheumatology (Oxford) Epub 2018 Aug 21.  Back to cited text no. 2
    
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World Health Organization. Latent TB Infection: Updated and Consolidated Guidelines for Programmatic Management. World Health Organization; 2018. Available from: http://www.who.int/tb/publications/2018/latent-tuberculosis-infection/en/. [Last accessed on 2018 Sep 09].  Back to cited text no. 3
    
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Buch MH, Smolen JS, Betteridge N, Breedveld FC, Burmester G, Dörner T, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis 2011;70:909-20.  Back to cited text no. 4
    
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Ash Z, Gaujoux-Viala C, Gossec L, Hensor EM, FitzGerald O, Winthrop K, et al. A systematic literature review of drug therapies for the treatment of psoriatic arthritis: Current evidence and meta-analysis informing the EULAR recommendations for the management of psoriatic arthritis. Ann Rheum Dis 2012;71:319-26.  Back to cited text no. 5
    
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Hatemi G, Christensen R, Bang D, Bodaghi B, Celik AF, Fortune F, et al. 2018 update of the EULAR recommendations for the management of behçet's syndrome. Ann Rheum Dis 2018;77:808-18.  Back to cited text no. 6
    
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Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two phase 3 trials of adalimumab for hidradenitis suppurativa. N Engl J Med 2016;375:422-34.  Back to cited text no. 7
    
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Delage M, Samimi M, Atlan M, Machet L, Lorette G, Maruani A, et al. Efficacy of infliximab for hidradenitis suppurativa: Assessment of clinical and biological inflammatory markers. Acta Derm Venereol 2011;91:169-71.  Back to cited text no. 8
    
9.
Tursi A. Concomitant hidradenitis suppurativa and pyostomatitis vegetans in silent ulcerative colitis successfully treated with golimumab. Dig Liver Dis 2016;48:1511-2.  Back to cited text no. 9
    
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Adams DR, Yankura JA, Fogelberg AC, Anderson BE. Treatment of hidradenitis suppurativa with etanercept injection. Arch Dermatol 2010;146:501-4.  Back to cited text no. 10
    
11.
Baughman RP, Drent M, Kavuru M, Judson MA, Costabel U, du Bois R, et al. Infliximab therapy in patients with chronic sarcoidosis and pulmonary involvement. Am J Respir Crit Care Med 2006;174:795-802.  Back to cited text no. 11
    
12.
Sweiss NJ, Noth I, Mirsaeidi M, Zhang W, Naureckas ET, Hogarth DK, et al. Efficacy results of a 52-week trial of adalimumab in the treatment of refractory sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2014;31:46-54.  Back to cited text no. 12
    
13.
Stagaki E, Mountford WK, Lackland DT, Judson MA. The treatment of lupus pernio: Results of 116 treatment courses in 54 patients. Chest 2009;135:468-76.  Back to cited text no. 13
    
14.
Shanmugam VK, DeMaria DM, Attinger CE. Lower extremity ulcers in rheumatoid arthritis: Features and response to immunosuppression. Clin Rheumatol 2011;30:849-53.  Back to cited text no. 14
    
15.
Brooklyn TN, Dunnill MG, Shetty A, Bowden JJ, Williams JD, Griffiths CE, et al. Infliximab for the treatment of pyoderma gangrenosum: A randomised, double blind, placebo controlled trial. Gut 2006;55:505-9.  Back to cited text no. 15
    
16.
Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, et al. Secukinumab in plaque psoriasis – Results of two phase 3 trials. N Engl J Med 2014;371:326-38.  Back to cited text no. 16
    
17.
Thaçi D, Blauvelt A, Reich K, Tsai TF, Vanaclocha F, Kingo K, et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J Am Acad Dermatol 2015;73:400-9.  Back to cited text no. 17
    
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Krupashankar DS, Dogra S, Kura M, Saraswat A, Budamakuntla L, Sumathy TK, et al. Efficacy and safety of itolizumab, a novel anti-CD6 monoclonal antibody, in patients with moderate to severe chronic plaque psoriasis: Results of a double-blind, randomized, placebo-controlled, phase-III study. J Am Acad Dermatol 2014;71:484-92.  Back to cited text no. 18
    
19.
Budamakuntla L, Madaiah M, Sarvajnamurthy S, Kapanigowda S. Itolizumab provides sustained remission in plaque psoriasis: A 5-year follow-up experience. Clin Exp Dermatol 2015;40:152-5.  Back to cited text no. 19
    
20.
Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016;75:1583-94.  Back to cited text no. 20
    
21.
Guillevin L, Pagnoux C, Karras A, Khouatra C, Aumaître O, Cohen P, et al. Rituximab versus azathioprine for maintenance in ANCA-associated vasculitis. N Engl J Med 2014;371:1771-80.  Back to cited text no. 21
    
22.
Oddis CV, Reed AM, Aggarwal R, Rider LG, Ascherman DP, Levesque MC, et al. Rituximab in the treatment of refractory adult and juvenile dermatomyositis and adult polymyositis: A randomized, placebo-phase trial. Arthritis Rheum 2013;65:314-24.  Back to cited text no. 22
    
23.
Merrill JT, Neuwelt CM, Wallace DJ, Shanahan JC, Latinis KM, Oates JC, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: The randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum 2010;62:222-33.  Back to cited text no. 23
    
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Hofmann SC, Leandro MJ, Morris SD, Isenberg DA. Effects of rituximab-based B-cell depletion therapy on skin manifestations of lupus erythematosus – Report of 17 cases and review of the literature. Lupus 2013;22:932-9.  Back to cited text no. 25
    
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Puéchal X, Gottenberg JE, Berthelot JM, Gossec L, Meyer O, Morel J, et al. Rituximab therapy for systemic vasculitis associated with rheumatoid arthritis: Results from the Autoimmunity and Rituximab Registry. Arthritis Care Res (Hoboken) 2012;64:331-9.  Back to cited text no. 27
    
28.
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29.
Khanna D, Denton CP, Jahreis A, van Laar JM, Frech TM, Anderson ME, et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): A phase 2, randomised, controlled trial. Lancet 2016;387:2630-40.  Back to cited text no. 29
    



 
 
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Abstract
Introduction
Biologicals and ...
Preliminary Conc...
Tumor-Necrosis-F...
Interleukin 17a ...
Itolizumab
Rituximab
Tocilizumab
Conclusion
References
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