Can tocilizumab deep six recalcitrant morphea?
By Warren R. Heymann, MD, FAAD
Sept. 20, 2023
Vol. 5, No. 38
Glenda’s middle-aged ankles still hurt badly. I have been treating morphea enveloping her ankles for several years. With therapies including methotrexate, mycophenolate mofetil, clobetasol, calcipotriene, and physical therapy, her tenderness has improved from exquisite to barely tolerable. Examining her lesions, I reminded myself of a question posed in the preface from every edition of Treatment of Skin Disease – “Now what do I do”? (1)
Morphea (localized scleroderma) is characterized by striking fibroplasia of the skin with potential extension to underlying subcutaneous tissue (morphea profunda) and bone (pansclerotic morphea). There are four main categories of morphea: circumscribed, generalized, pansclerotic, and linear (which is subdivided into head [“en coup de sabre” ECDS] and trunk/extremity variants). (2) ECDS may be associated with the Parry Romberg syndrome characterized by progressive facial hemiatrophy involving the skin, subcutaneous tissue, muscles, and bones. (3) The considerable functional impairment and cosmetic disfigurement of morphea adversely affects the quality of life. (4)
Therapeutic and reconstructive management options for ECDS have been reviewed by Ulc et al in a systematic review. As excerpted from their abstract: “Methotrexate was the most commonly investigated treatment (26 patients) with a highest response rate (26/26, 100%). Other treatments included systemic glucocorticosteroids (nine patients), followed by UVA1 (four patients), mycophenolate mofetil (two patients), hydroxychloroquine (five patients), abatacept (two patients), tocilizumab (three patients), cyclosporine (one patient), interferon gamma (one patient), PUVA therapy (two patients), NB-UVB therapy (one patient), and pulsed dye laser (one patient). Reconstructive and surgery treatment was successfully used for lesions with settled disease activity to improve the cosmetic aspect of the lesions.” (5) There has been increasing literature regarding the use of tocilizumab (Actemra) for morphea, which will be the focus of this commentary.
The etiology of morphea is unknown, although genetic predisposition, autoimmune dysregulation, and environmental factors (trauma, radiation, and friction) play a role in its pathogenesis. The presence of auto-antibodies (ANA), anti-single-stranded DNA, and anti-histone antibodies) supports the role of autoimmune dysregulation. (6)
While multiple cytokines may influence cutaneous fibrosis, IL-6 is a critical cytokine in this process. (7). IL-6 is a proinflammatory cytokine that regulates fibroblast activity, stimulates collagen production, and inhibits the formation of collagenases. (8) IL-6 is produced from multiple sources, including dendritic cells, macrophages, T and B lymphocytes, fibroblasts, and epithelial cells. IL-6 binds to the IL-6 receptor/gp130 complex, which then activates intracellular signaling cascades via the signaling molecules JAK1 and STAT3. Tocilizumab is humanized monoclonal antibody to the IL-6 receptor and competitively inhibits the binding of IL-6 to both membrane-bound and soluble IL-6 receptors. (9) Tocilizumab is currently FDA–approved for systemic sclerosis-associated interstitial lung disease, giant cell arteritis, juvenile idiopathic arthritis (polyarticular and systemic), rheumatoid arthritis, cytokine release syndrome, and COVID-19. (8)
Tocilizumab has recently been reported to be beneficial in patients with the following morphea variants that were refractory to standard therapies (all are case reports or small case series): juvenile localized scleroderma (10), pansclerotic morphea (11, 12), ECDS and Parry Romberg (2,3,13), and checkpoint inhibitor-induced generalized morphea. (14) Tocilizumab may be effective in adults with recalcitrant morphea as well as children. Tocilizumab is available as a monthly intravenous infusion or a weekly subcutaneous injection. Initial clinical improvement on tocilizumab was noted after an average of 2.8 months. (15)
Tocilizumab is generally well-tolerated. Common adverse effects include infections (cellulitis, urinary tract, and respiratory tract), gastrointestinal (nausea, vomiting, diarrhea, elevated transaminases, and rarely lower intestinal bowel perforation), and hyperlipidemia (cholesterol and triglycerides). Rare adverse effects include cytopenias and malignancies (with keratinocyte carcinomas most frequently reported). (9)
In conclusion, tocilizumab may be a valuable therapeutic option for patients with morphea recalcitrant to standard treatments. Only prospective, double-blinded, randomized trials will adequately assess its utility. Morphea can be devastating; it would be worthwhile to know if early administration of tocilizumab could prevent disease progression. More study is essential. Until we have such data, I will consider prescribing tocilizumab for patients like Glenda.
Point to Remember: The IL-6 inhibitor tocilizumab may have a therapeutic role in cases of recalcitrant morphea.
Our experts’ viewpoint
Dean J. Choong, MD
Department of Dermatology, Fiona Stanley Hospital, Western Australia
Western Australian Faculty, The Australasian College of Dermatologists
Ernest Tan, MBBS, FACD
Department of Dermatology, Sir Charles Gairdner Hospital, Western Australia
Western Australian Faculty, The Australasian College of Dermatologists
This is a great article by Dr. Heymann and we’re extremely honored to contribute to the Experts’ Viewpoint. Morphea, when recalcitrant, is a very difficult condition to manage and can have a profound impact on patients’ quality of life, particularly when it affects functionally and cosmetically sensitive areas. Tocilizumab has its use in rheumatology as a well-tolerated treatment. Within dermatology, in recent years, dermatoses with an autoimmune or inflammatory basis have demonstrated response to newer biologic and small-molecule inhibitor agents. It seems that tocilizumab (an anti-IL-6R) for morphea (where IL-6 is proposed to play a key role in fibrosis) could be therapeutically effective.
We read with great interest the recent case series by Lonowski et al. (15) describing the dramatic response of recalcitrant morphea in 3 adult patients treated with tocilizumab, which adds to the evidence of previously reported cases. It was also interesting to note that those who had a shorter duration of morphea tended to have a more rapid response to tocilizumab. These reports are certainly exciting, however, there is a temptation to think “why not put everyone with difficult morphea on tocilizumab?” These treatments often come at a significant financial cost and while safe, are not entirely risk-free. Additionally, we should strive toward evidence-based practice whenever possible. These case reports pave the way for larger randomised studies to be conducted, which hopefully include objective measures of disease such as the mLoSSI (modified Localized Scleroderma Skin Severity Index) and DLQI. A double-blinded, placebo-controlled phase II trial of Tocilizumab in systemic sclerosis demonstrated statistically non-significant improvements in cutaneous involvement, but the subsequent phase III trial did not meet its endpoint for cutaneous improvement.
Important questions which can only be answered with more clinical evidence are “when in the disease course should tocilizumab be trialled?”, and “should tocilizumab be monotherapy or adjunctive therapy?” In the interim, we agree that select patients with severe, recalcitrant, debilitating disease could be considered for a careful trial of therapy, particularly when a concurrent rheumatological indication is present, such as rheumatoid arthritis (as did one patient in Lonowski et al.’s study). (15)
Lebwohl MG, Heymann WR, Coulson IH, Murrell DF. Preface. In Lebwohl MG, Heymann WR, Coulson IH, Murrell DF (eds). Treatment of Skin Disease, sixth edition. Elsevier, London, 2022, pp xi.
Magro CM, Halteh P, Olson LC, Kister I, Shapiro L. Linear scleroderma "en coup de sabre" with extensive brain involvement-Clinicopathologic correlations and response to anti-Interleukin-6 therapy. Orphanet J Rare Dis. 2019 May 16;14(1):110. doi: 10.1186/s13023-019-1015-7. PMID: 31096996; PMCID: PMC6524280.
Meneghetti TC, da Silva JYB, Kluppel LE, de Carvalho VO. Parry Romberg disease with En Coup de Sabre Scleroderma: Effect of tocilizumab on periodontal bone inflammation. J Scleroderma Relat Disord. 2021 Jun;6(2):206-210. doi: 10.1177/2397198320975872. Epub 2020 Nov 25. PMID: 35386743; PMCID: PMC8892937.
Bali G, Kárpáti S, Sárdy M, Brodszky V, Hidvégi B, Rencz F. Association between quality of life and clinical characteristics in patients with morphea. Qual Life Res. 2018 Oct;27(10):2525-2532. doi: 10.1007/s11136-018-1897-1. Epub 2018 Jun 19. PMID: 29922914.
Ulc E, Rudnicka L, Waśkiel-Burnat A, Warszawik-Hendzel O, Niemczyk A, Olszewska M. Therapeutic and Reconstructive Management Options in Scleroderma (Morphea) en Coup de Sabre in Children and Adults. A Systematic Literature Review. J Clin Med. 2021 Sep 29;10(19):4517. doi: 10.3390/jcm10194517. PMID: 34640533; PMCID: PMC8509267.
Penmetsa GK, Sapra A. Morphea. 2022 Aug 8. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–. PMID: 32644436.
Stephens MR, Moore DF, Dau J, Jobbagy S, Neel VA, Bolster MB, Fedeles F. A case of generalized morphea profunda following SARS-CoV-2 infection. JAAD Case Rep. 2022 May;23:20-23. doi: 10.1016/j.jdcr.2022.02.033. Epub 2022 Mar 12. PMID: 35308063; PMCID: PMC8917007.
Sloan SB. This Month in JAAD Case Reports: March 2023: Tocilizumab for refractory morphea. J Am Acad Dermatol. 2022 Dec 29:S0190-9622(22)03319-9. doi: 10.1016/j.jaad.2022.12.028. Epub ahead of print. PMID: 36586486.
Choong DJ, Tan E. Does tocilizumab have a role in dermatology? A review of clinical applications, its adverse side effects and practical considerations. Dermatol Ther. 2021 Jul;34(4):e14990. doi: 10.1111/dth.14990. Epub 2021 May 25. PMID: 34004074.
Lythgoe H, Baildam E, Beresford MW, Cleary G, McCann LJ, Pain CE. Tocilizumab as a potential therapeutic option for children with severe, refractory juvenile localized scleroderma. Rheumatology (Oxford). 2018 Feb 1;57(2):398-401. doi: 10.1093/rheumatology/kex382. PMID: 29077971.
Martini G, Campus S, Raffeiner B, Boscarol G, Meneghel A, Zulian F. Tocilizumab in two children with pansclerotic morphoea: a hopeful therapy for refractory cases? Clin Exp Rheumatol. 2017 Sep-Oct;35 Suppl 106(4):211-213. Epub 2017 Sep 29. PMID: 28980909.
Zhang A, Nocton J, Chiu Y. A Case of Pansclerotic Morphea Treated With Tocilizumab. JAMA Dermatol. 2019 Mar 1;155(3):388-389. doi: 10.1001/jamadermatol.2018.5040. PMID: 30649148.
Osminina M, Geppe N, Afonina E. Scleroderma "en coup de sabre" With Epilepsy and Uveitis Successfully Treated With Tocilizumab. Reumatol Clin (Engl Ed). 2020 Sep-Oct;16(5 Pt 1):356-358. English, Spanish. doi: 10.1016/j.reuma.2018.05.001. Epub 2018 Jul 9. PMID: 29929808.
Blaise M, Cardot-Leccia N, Seitz-Polski B, Picard-Gauci A, Bertold C, Passeron T, Montaudié H. Tocilizumab for Corticosteroid-Refractory Immune Checkpoint Inhibitor-Induced Generalized Morphea. JAMA Dermatol. 2023 Jan 1;159(1):112-114. doi: 10.1001/jamadermatol.2022.5146. PMID: 36449277.
Lonowski S, Goldman N, Kassamali B, Shahriari N, LaChance A, Vleugels RA. Tocilizumab for refractory morphea in adults: A case series. JAAD Case Rep. 2022 Oct 4;30:27-29. doi: 10.1016/j.jdcr.2022.09.024. PMID: 36353292; PMCID: PMC9637845.
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