|Year : 2022 | Volume
| Issue : 5 | Page : 568-572
|Anti CD-6 monoclonal antibodies in the management of generalised pustular psoriasis
Mahendra M Kura, Anmol Sodhi, Avinash Sajgane, Ashish Karande
Department of Dermatology, Venereology and Leprosy, Grant Government Medical College, Sir JJ Group of Hospitals, Mumbai, Maharashtra, India
|Date of Web Publication||29-Dec-2022|
Skin OPD 42, Main OPD Building, JJ Hospital, Byculla, Mumbai, Maharashtra - 400 008
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Generalised pustular psoriasis (GPP) is an uncommon, severe, life-threatening variant of psoriasis requiring careful therapeutic approach. Conventional treatment modalities have unsatisfactory outcomes, poor side effect profiles and toxicities that have led to an emerging use of biological therapies. Itolizumab, an anti-CD-6 humanised monoclonal IgG1 antibody, is approved for the management of chronic plaque psoriasis in India. We share our experience of using this drug in three cases of GPP that were failing conventional therapies. Its upstream effect on co-stimulatory pathway in disease pathogenesis is the postulated mechanism. Our experience warrants further large-scale exploration of the role of itolizumab in the management of GPP, which would benefit this severely affected population of patients. Although the definite pathogenesis of GPP is unknown fully, molecules blocking CD-6, which plays a role in the interaction between T cells and antigen-presenting cells (APCs), are expected as new promising treatment options for GPP.
Keywords: Anti-CD-6, biological agents, generalised pustular psoriasis, humanised IgG1 monoclonal antibody, itolizumab
|How to cite this article:|
Kura MM, Sodhi A, Sajgane A, Karande A. Anti CD-6 monoclonal antibodies in the management of generalised pustular psoriasis. Indian J Dermatol 2022;67:568-72
|How to cite this URL:|
Kura MM, Sodhi A, Sajgane A, Karande A. Anti CD-6 monoclonal antibodies in the management of generalised pustular psoriasis. Indian J Dermatol [serial online] 2022 [cited 2023 Jan 30];67:568-72. Available from: https://www.e-ijd.org/text.asp?2022/67/5/568/366107
| Introduction|| |
Psoriasis is a common, chronic, inflammatory disease of the skin clinically characterised by well-demarcated, red, scaly, indurated plaques. It is now recognised as an important non-communicable disease. In addition to this common chronic plaque form of disease, several other subtypes including pustular forms are seen rarely. Generalised pustular psoriasis (GPP) is one such rare type of disease characterised by the presence of sterile pustules in a generalised distribution that was first described almost 100 years ago. It is an extreme form of psoriasis which is often associated with systemic disturbances like fever and arthralgia and can be life threatening. Acute form of GPP is named after Leo von Zumbusch, who first described the disease in 1910. This disease may occur de novo or in patients of chronic plaque psoriasis insulted by topical coal tar or other irritants, sudden withdrawal of corticosteroids, stress, pregnancy, hypocalcaemia, infections and so on. The disease is associated with various complications like hypoalbuminemia, hypocalcaemia, oligaemia, renal tubular necrosis, haemodynamic instability, liver damage, cardiorespiratory failure and even death in extreme cases. The disease also has significant social and psychological implications and has a negative impact on the quality of life (QOL) of patients.
Though little is known of the pathogenesis of GPP as well as its similarity to psoriasis vulgaris, treatments are often borrowed from it. Management of GPP includes withdrawal of provocative factors, general measures like hospital admission with bed rest, fluid and protein replacement, preventing excessive heat loss and bland topical applications. Systemic therapy includes retinoids, cyclosporine, methotrexate and Psoralen + ultraviolet light A (PUVA) therapy., However, these conventional therapies have their limitations and are associated with multiple side effects and also are unsatisfactory to date. There is an emerging need for the use of better treatment options like biological agents. Though none of the biological agents are still approved for GPP, several of them like tumour necrosis factor (TNF) antagonists, basiliximab and brodalumab are being used. These, along with having a better side effect profile, have the added advantage of rapid action and excellent control of disease.
Itolizumab is one such biological agent which is a humanised monoclonal IgG1 antibody that recognises the distal domain of CD6, a highly glycosylated membrane protein predominantly expressed on lymphocytes. It is an upstream blocker which inhibits the co-stimulation of T cells, thereby decreasing the release of cytokines by Th1 and Th17 cells which have a very important role in the disease pathogenesis. Itolizumab also does not cause any paradoxical exacerbation of GPP, like TNF antagonists. It is approved for use in psoriasis vulgaris in India, and we hereby share our experience of its use in three cases of GPP.
| Case Reports|| |
Three patients with the clinical diagnosis of GPP were admitted in our ward. A detailed history was taken including the disease duration, previous therapies taken and the side effects observed after taking them. Past history of any comorbid conditions and probable precipitating factors for the disease were also inquired [Table 1]. Their disease severity was assessed clinically and scored using pustular symptom score evaluation and scoring system in pustular psoriasis. The scoring system in pustular psoriasis, developed by Ohkawara et al., is based on assessment of severity of dermal symptoms and lab parameters (fever, erythrocyte sedimentation rate (ESR), white blood cell (WBC), serum albumin, serum calcium levels), and the pustular symptom score evaluation is based on severity of skin and systemic symptoms and laboratory findings (WBC, C- reactive protein (CRP), serum albumin). An informed consent was obtained from all three patients, and periodic photographs of the patients were taken, including at baseline and at each visit. Patients were thoroughly investigated. Itolizumab was administered intravenously at a dose of 1.6 mg/kg every 2 weeks for 12 weeks, followed by every 4 weeks for 12 weeks. The improvement was measured by clinical examination, regular photographs and scores which were recorded using both the scoring systems at each visit. Patients were monitored for side effects of the drug and for disease relapse. All the data obtained was documented in case record formats. These patients are on a regular follow-up subsequently for the development of any adverse effects.
|Table 1: Demographics, clinical characters at baseline, adverse events to itolizumab|
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Case 1 was a 12-year-old female who was a case of juvenile pustular psoriasis since the age of 5 years. She had severe nail involvement with dystrophy of all 20 nails. She was initially started on weekly tablet methotrexate, but had a minimal disease improvement. She was given systemic steroids intermittently multiple times for the control of acute flares of the disease. This led to weight gain and Cushingoid habitus. Cyclosporine was also tried for disease control, but the patient developed hypertension due to the drug. As she was failing conventional therapies in addition to developing drug-related side effects, she was administered the full regimen of intravenous itolizumab therapy. She tolerated the infusions well and had a complete clearance of the skin and systemic symptoms [Figure 1] and [Figure 2]. However, the disease relapsed after 4 months of therapy completion, though the severity and area of involvement were much less compared to baseline. Nails did not show any improvement at any time during therapy or post-therapy completion [Figure 3].
|Figure 1: (a) The pustular symptom score of all three patients at each dose and also at 1 month after the last dose. (b) The scoring system for pustular psoriasis score at each Itolizumab dose and also at 1 month after the last dose (mth = month)|
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|Figure 2: Case 1 showing (a) Multiple pustules forming lakes of pus over trunk, both upper limbs before the start of Itolizumab; (b) After 6th infusion the pustules cleared leaving behind areas of hypopigmentation; (c) After 10th infusion there was complete clearance of pustules and post inflammatory hypopigmentation also subsided|
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|Figure 3: (a) 20-nail dystrophy before starting Itolizumab in Case 1; (b) Persistence of 20-nail dystrophy after completion of Itolizumab infusions; (c)Persistence of flexural disease in Case 2 after completion of Itolizumab infusions|
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Case 2 was a 30-year-old female who was an old case of juvenile pustular psoriasis since the age of 5 years and had a complete disease clearance on intermittent steroids by 10 years of age. However, the disease recurred 1 month after her first delivery, 7 years back, for which she was given systemic steroids and had a complete clearance of lesions. The disease again recurred in her second pregnancy at 9 months ante-partum period when she presented to us. On examination, she had extensive cutaneous involvement in the form of generalised pustules and erythema, flexural disease, 20-nail dystrophy and telogen effluvium. She was treated with systemic steroids, due to which she subsequently developed steroid-induced myopathy and recurrent oral candidiasis. Due to these complications, she was given itolizumab therapy. She tolerated the infusions well, and the pustules and nail dystrophy started clearing after the second infusion and were completely cleared by the end of therapy [Figure 1] and [Figure 4]. However, the flexural disease persisted [Figure 3]. Patient had a disease-free interval of 1 year, after which she had a recurrence of pustules, this time following a missed abortion.
|Figure 4: showing (a) Multiple discrete and confluent pustules on thighs before start of Itolizumab; (b) After 6th infusion there was complete clinical clearance; (c) Clearance maintained after 10th infusion also|
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Case 3 was a 54-year-old female who was a newly diagnosed case of acute GPP with disease duration of 5 months. She had a body mass index (BMI) of 37 kg/m2 and was class-II obese. She was a known hypertensive and also had hypothyroid disorder since many years. Because of her coexistent comorbid conditions, she was given a full course of itolizumab therapy. She tolerated the infusions well and there was a complete clearance of pustules after the fifth dose; but there was recurrence after 1 year of completion of therapy [Figure 1] and [Figure 5]. The recurrence in this case was also much less severe than that of baseline and was mild disease as per the pustular symptom score evaluation and moderate as per the scoring system in pustular psoriasis.
|Figure 5: Case 3 showing (a) multiple pustules on upper limbs before the start of Itolizumab; (b) After 6th infusion there was clearance of pustules but persistence of erythema; (c) After 10th infusion there was complete clearance of pustules as well as erythema|
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(Pustular symptom score evaluation and scoring system in pustular psoriasis of all three patients decreased, as shown in [Figure 1]) None of the patients had infusion reaction or reactivation of any latent tuberculosis (TB) or a new infection. None of the patients had exacerbation of disease severity after any infusion. None of the patients experienced any serious adverse effects. Thus, itolizumab was a safe and effective therapeutic agent for the management of GPP in all our three cases.
| Discussion|| |
GPP is a severe, serious and potentially life-threatening condition which must be adequately and quickly treated. It is a rare disease, which is estimated to affect 1% of all psoriatic patients. Acute GPP (von Zumbusch disease), GPP of pregnancy, infantile and juvenile pustular psoriasis, circinate, annular and linear pustular psoriasis and localised forms of GPP are the variants of GPP. Our three cases belonged to the first three groups.
The current management options for GPP are retinoids, cyclosporine and methotrexate. Various biological agents are also being explored. However, the treatment still remains unsatisfactory with lack of universally accepted, evidence-based guidelines and lack of sound scientific data on the disease pathogenesis and clinical behaviour.
The pathogenesis of GPP is still unknown, though it shares a few pathways with psoriasis vulgaris in the inflammatory cascade with heavier neutrophilic infiltrates. GPP is driven by the innate arm of the immune system., Few of the major molecules involved are IL-23/Th17 axis, IL-6 and IL-36 RN mutations.,,, There is a role of CD-6 in the pathogenesis of psoriasis, which is a surface glycoprotein found on the outer surface of mature T cells and immature B cells.,,,, Its extracellular region has three scavenger receptor cysteine-rich (SRCR) domains (D). T and B lymphocytes and antigen presenting cells (APC) express activated leucocyte cell adhesion molecule (AL CAM), which is a ligand for CD 6.,,,, This ALCAM binds with the SRCR of CD-6, and thus helps in the interaction between T cells and APCs.,,, This immunological synapse leads to the differentiation, proliferation and maturation of T cells. CD-6 also increases the release of TNF-α, interferon gamma (IFN-γ) and IL-6, which leads to keratinocyte activation and acanthosis, hyperkeratosis and parakeratosis histopathologically.
Itolizumab is a humanised recombinant monoclonal IgG1 antibody, which is anti-CD-6 and targets SRCR of CD-6 present on the surface of T cells. It thus acts as an upstream inhibitor and decreases the release of key cytokines of Th1 and Th17 cells., The molecule is composed of two heavy chains with 449 amino acids and two light chains with 214 amino acids, which are linked via a disulphide bond.
Our first patient, a case of juvenile GPP, suffering from the disease since the age of 5 years, was responding poorly to methotrexate and developed hypertension due to cyclosporine and Cushingoid habitus due to systemic steroids. She improved significantly from the first itolizumab infusion and the disease severity also decreased gradually. By the end of all infusions, the disease activity was mild as per both the scoring systems used. The number and severity of recurrences post-infusion completion also reduced significantly. However, her 20-nail dystrophy showed no improvement [Figure 3].
Our second case (GPP of pregnancy) developed generalised pustules in her each pregnancy. Her worsening symptoms and weight gain due to steroids made us to start itolizumab for her, and she started improving from the second infusion and showed almost complete cutaneous clearance by the fourth infusion. However, her flexural disease remained resistant to itolizumab [Figure 3].
Our third case (acute GPP) was started on itolizumab because of her coexistent hypertension, which would have worsened with conventional modalities like steroids and cyclosporine. She also had a remarkable clearance of lesions starting from the second infusion itself and a marked decrease in disease severity from severe to mild by the end of completion of infusions.
Thus, itolizumab, by acting as an upstream inhibitor in disease pathogenesis, can control the disease at early stages of initiation. As was seen in all our three cases, patients had clearance of lesions and decrease in disease severity shortly after the start of therapy. Therefore, itolizumab was found to be having efficacy in rapidly controlling the disease and having good side effect profile as seen in our cases, making it a suitable option for use in GPP. Our experience warrants further studies to establish its role. However, as in our cases, the nails showed minimal improvement and flexural disease responded poorly to itolizumab, a constant search for newer treatment agents is required, which would also overcome these challenges.
We would like to thank Dr. Alok Rasal and Dr. Swaroop H. S. from Biocon India Ltd. for providing injection itolizumab for these patients on our request for academic interest.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
What was known? Generalised pustular psoriasis (GPP) is a severe, life threatening condition that requires a prompt therapeutic approach. It is long being managed by conventional immunosuppressive and immunomodulatory drugs with limited benefits and multiple adverse effects, which add to the morbidities of patients affected with psoriasis.
What is new? Itolizumab, approved in India for the management of plaque psoriasis, is an anti-CD-6 monoclonal antibody having an upstream inhibitory effect on co-stimulatory pathway in the early stages of GPP pathogenesis. It is a therapeutic option which should be further explored by conducting large-scale studies.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
von Zumbusch LR. Psoriasis and pustulosis Exanthem. Arch Dermatol Syphilol 1910;99:335-46.
Ogawa M, Baughman RD, Clendenning WE. Generalized pustular psoriasis. Arch Dermatol 1969;99:671-3.
Feiwel M, Ferriman D. Impetigo herpetiformis. Proc R Soc Med 1957;50:392-4.
Risum G. Psoriasis exacerbated by hypoparathyroidism with hypocalcemia. Br J Dermatol 1973;89:309-12.
Baker H, Ryan TJ. Generalized pustular psoriasis. Br J Dermatol 1968;80:771-93.
Gooderham MJ, Van Voorhees AS, Lebwohl MG. An update on generalized pustular psoriasis. Expert Rev Clin Immunol 2019;15:907-19.
Umezawa Y, Ozawa A, Kawasima T, Shimizu H, Terui T, Tagami H, et al. Therapeutic guidelines for the treatment of generalized pustular psoriasis (GPP) based on a proposed classification of disease severity. Arch Dermatol Res. 2003 Apr;295 Suppl 1:S43-54.
Yamasaki K, Nakagawa H, Kubo Y, Ootaki K; Japanese Brodalumab Study Group. Efficacy and safety of brodalumab in patients with generalized pustular psoriasis and psoriatic erythroderma: Results from a 52-week, open-label study. Br J Dermatol 2017;176:741-51.
Iwatsuki K, Terui T, Ozawa A, Komiyane M, Umezawa K, Torii H, et al
. Practice guidelines 2010 for generalized pustular psoriasis (GPP): Treatment guidelines incorporating TNF-a inhibitor. Jpn J Dermatol 2010;120:815-39. (Japanese).
Menon R, David BG. Itolizumab-a humanized anti-CD6 monoclonal antibody with a better side effects profile for the treatment of psoriasis. Clin Cosmet Investig Dermatol 2015;8:215-22.
Johnston A, Xing X, Wolterink L, Barnes DH, Yin Z, Reingold L, et al
. IL-1 and IL-36 are dominant cytokines in generalized pustular psoriasis. J Allergy Clin Immunol 2017;140:109-20.
Liang Y, Xing X, Beamer MA, Swindell WR, Sarkar MK, Roberts LW, et al
. Six-transmembrane epithelial antigens of the prostate comprise a novel inflammatory nexus in patients with pustular skin disorders. J Allergy Clin Immunol 2017;139:1217-27.
Furue K, Yamamura K, Tsuji G, Mitoma C, Uchi H, Nakahara T, et al
. Highlighting interleukin-36 signalling in plaque psoriasis and pustular psoriasis. Acta Derm Venereol 2018;98:5-13.
Ogawa E, Sato Y, Minagawa A, Okuyama R. Pathogenesis of psoriasis and development of treatment. J Dermatol 2018;45:264-72.
Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH, Pullabhatla V, et al
. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am J Hum Genet 2011;89:432-7.
Nair P, Melarkode R, Rajkumar D, Montero E. CD6 synergistic costimulation promoting proinflammatory response is modulated without interfering with the activated leucocyte cell adhesion molecule interaction. Clin Exp Immunol 2010;162:116-30.
Alonso-Ramirez R, Loisel S, Buors C, Pers JO, Montero E, Youinou P, et al
. Rationale for targeting CD6 as a treatment for autoimmune diseases. Arthritis 2010;2010:130646.
Dogra S, Uprety S, Suresh SH. Itolizumab, a novel anti-CD6 monoclonal antibody: A safe and efficacious biologic agent for management of psoriasis. Expert Opin Biol Ther 2017;17:395-402.
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.
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