Begetting, Begatting, Conflating: Localized scleroderma sub-types proliferated without clarifying disease process.
In searching for the diagnostic criteria for Localized scleroderma, I fetched up a 2018 criteria set developed by the same authors who proposed an as-yet-unvalidated diagnostic criteria for Eosinophilic fasciitis (for more information on Eosinophilic fasciitis, check out my Diagnosis Description here). Since 1961, defining a list of sub-types of Localized scleroderma has been the method for defining Localized scleroderma. A note about terms: “Localized scleroderma” and “Morphea” have often been used as synonyms in the scientific literature. I prefer “Localized scleroderma” to “Morphea” because so much of what defines Localized scleroderma is in what differentiates it from Systemic sclerosis. So, even though the scientific evidence points to these being different disease processes, I consider them inextricably linked under the broad umbrella of “Scleroderma,” only to be cleaved in the future by proven differentiation at a genetic, environmental and immune dysfunction level.
Frankly, it’s astonishing to me that up until 2018, Localized scleroderma, as an overarching category, was exclusively defined by its various lists of sub-types. The following set of criteria for Localized scleroderma has not been validated—and it’s far from a consensus criteria. I don’t know whether, or to what effect, it has been adopted in clinical practice, or as the inclusion criteria for scientific studies of Localized scleroderma, but I’ll be looking out for that going forward. Do I wish there was an international consensus diagnostic criteria that included multitudes of experts, and had been used as the basis for consistent comparative scientific studies for at least the last five years? I sure do. It’s a little exasperating that this isn’t the case. But, I appreciate that these authors out of Japan recognized the need for criteria, and published their best proposal, using a detailed methodology based on the robotic, vaguely-biblical, new age-y sounding title: New Minds Clinical Practice Guideline Creation Manual (version 1.0). It’s an amusing relief to know that they applied an awkwardly-titled method to the madness.
Juvenile idiopathic arthritis is an object lesson in what can happen when an organization publishes workable scientific study classification criteria. Even though the study classification criteria for Juvenile idiopathic arthritis is flawed, it has provided the basis for 20 years of accumulated scientific evidence. That evidence is now being used to create more accurate study classification criteria. And if you’re reading this and thinking, boy, that’s a long road…to better science. I hear you, but the more evidence-based a study classification criteria becomes, the closer it gets to becoming validated diagnostic criteria. When study classification criteria and diagnostic criteria scientifically converge, the result is earlier, faster and better diagnostic testing, better and more treatment options, the chance at early identification and prevention of severe disease. After all, if you can’t define it, you can’t meaningfully study it. If you can’t study it, you can’t find an evidence base for its disease-causing mechanisms, prevalence in the population, disease course, prognosis, or best treatment options. Lack of criteria results in an inevitable trial and error clinical approach that has failed patients, and continues to do so.
Localized Scleroderma: The Criteria
After my impassioned argument for any study classification criteria, even if it’s flawed, I have to address the fact that the following is a proposed Diagnostic criteria. Diagnostic criteria can be used for study classification criteria, but is meant to be flexible enough to be used in a clinical setting. For now, something is better than nothing:
“Cases must satisfy all three of the following items:
Presence of sclerodermatous skin changes with circumscribed borders
Histopathological examination shows thickened and increased collagen fibers in the dermis
The following diseases can be excluded (however, this excludes cases in which the following diseases occur concurrently): systemic sclerosis, eosinophilic fasciitis, lichen sclerosus et atrophicus, keloid, (hypertrophic) scars and sclerosing panniculitis.”
(Asano et. al, 2018)
My review of the criteria:
Requirement #1 is broad, refers to “hard skin” changes with defined borders.
These biopsy requirements are broad, but not so broad as to be meaningless.
This exclusion criteria could be problematic if Eosinophilic fasciitis does prove to be within the spectrum of disease. The other exclusion criteria are better supported by the evidence.
Localized Scleroderma Sub-Types Are Like the Book of Genesis
Back to the historical definition of Localized scleroderma as lists of sub-types. All of the begets and begats are difficult to track—and hard to determine which sub-type cannon is, in fact, useful to accurate diagnosis and treatment. Asano et. al explore the history of the sub-types of Localized scleroderma in great detail here, in order to arrive at what they think is the most useful “classification” system, but these winding lists of sub-types are still largely grouped by how the lesions look to the naked eye, and how deep they go in the body—without clarifying the underlying disease mechanisms—possibly shared, possibly distinct. Despite the massive amount of work the authors put in to elucidating the different sub-types to justify their pick of the most useful list, the result is still confounded by its focus on visual appearance and level of tissue involvement. These sub-type lists are defined by the diagnostic tools that have been readily available for almost a century—a dermatologist looking at a lesion and taking a biopsy—not by the components of the underlying disease process. Let’s take a closer look, keeping in mind that most of the obscure terminology you’re about to encounter is simply a latin term for how a lesion looks to the naked eye—nothing more complicated than that:
Tuffanelli and Winkelmann classification (1961)
Morphea
“characterized by circumscribed, sclerotic plaques with an ivory-colored center and surrounding violaceous halo.
Punctate morphea is considered to be a variant of morphea, in which there appear small plaque complexes”
Linear scleroderma
“appears in a linear, band-like distribution, and scleroderma en bondes is a synonym of linear scleroderma. Frontal or frontoparietal linear scleroderma (en coup de sabre) is characterized by atrophy and a furrow or depression that extends below the level of the surrounding skin”
Generalized morphea
“the most severe form of localized scleroderma, is characterized by widespread skin involvement with multiple indurated plaques, hyperpigmentation and frequent muscle atrophy”
Generalized morphea classification criteria proposed by Sato et al (1994)
“A case is classified as having generalized morphea if both the following criteria are satisfied:
Four or more skin lesions that measure 3 cm or more in diameter (irrespective of whether the skin lesions are patchy or linear)
The skin lesions are distributed in two or more sites of the seven regions of the body (head and neck, left and right upper limbs, trunk front and back, and left and right lower limbs).
If the above criteria are not satisfied simultaneously, the condition is classified as morphea or linear scleroderma based on the morphological characteristics of the skin lesions”
Peterson et al. classification (1995)
Plaque morphea
Plaque morphea
Guttate morphea
Atrophoderma of Pasini and Pierini
Keloid morphea (nodular morphea)
(Lichen sclerosus et atrophicus)
Generalized morphea
Bullous morphea
Linear morphea
Linear morphea (linear scleroderma)
Morphea en coup de sabre
Progressive facial hemiatrophy
Deep morphea
Morphea profunda
Subcutaneous morphea
Eosinophilic fasciitis
Pansclerotic morphea of childhood
This criteria is rejected by Asano et. al “because it includes diseases for which a consensus had not been reached in terms of the spectrum of this condition (atrophoderma of Pasini and Pierini, lichen sclerosus et atrophicus and eosinophilic fasciitis), and this classification also does not have a proposal for which disease type a case should be classified if it satisfies more than one characteristic” (2018).
Padua Consensus classification (2004)
Circumscribed morphea
Superficial
Deep
Linear scleroderma
Trunk/limbs
Head
Generalized morphea
Pansclerotic morphea
Mixed morphea
“The Padua Consensus classification is dual, which means that the boundaries between individual disease types are somewhat blurred, but it is considered to be useful in clinical practice because by adding the histological criteria, it clearly categorizes the clinically important disease types, such as circumscribed morphea/deep variant and pansclerotic morphea. If we consider that the Padua Consensus classification is used as the global standard for classification of localized scleroderma disease types, we recommend classifying localized scleroderma into five different disease types: circumscribed morphea, linear scleroderma, generalized morphea, pansclerotic morphea and mixed morphea. The evidence level is low, but the recommendation level is set as 1D, based on the consensus of the committee that created this guideline.” (Asano et. al, 2018)
What’s Confounding Is
Most of these sub-types, in their various forms, show up in the studies I’ve read so far on Localized scleroderma. Even if study authors adhere to one sub-type list for their study inclusion criteria, they’re still using other terms to characterize sub-sets of their study population. Perhaps this disarray is okay—in that it allows for observations specific to an obscure sub-type that might not otherwise make it into the scientific record. What I struggle with is consistency from study to study—and the basic coherence of an author’s findings, when bits and pieces from other sub-type lists make it into the charts and narrative of their study.
Next week, I want to know and write more about Generalized morphea. It’s a seemingly distinct entity characterized in every sub-type list created since 1961. I’ve already seen evidence in one study on HLA associations in Localized scleroderma, that Generalized morphea has a distinct HLA association that differentiates it from other Localized scleroderma sub-types. I definitely want to know more about that, and whether more recent evidence backs up this difference.
For those who are new to AutoimmuneDx, I am currently writing posts based on reader-requests for more information and analysis on particular autoimmune diagnoses. I base my posts on the questions, concerns and—yes, feelings—that come up while completing a Diagnosis Description (you can read more about what goes into a Diagnosis Description here). Diagnosis Descriptions are designed to be a catalog of information that effectively describes and organizes the scientific evidence on autoimmune disease for people without a medical background. If you would like me to take a closer look at a particular diagnosis, please leave a comment below. If you don’t feel comfortable commenting publicly, email me at autoimmunedx@gmail.com. Because I have a curious mind and a medical background, I sometimes get too wrapped up in the weeds of autoimmune disease, so if you would like me to clarify a post, a concept, a word, or anything in-between, please don’t hesitate to leave a comment or send an email.
Reference
Asano, Y., Fujimoto, M., Ishikawa, O., Sato, S., Jinnin, M., Takehara, K., Hasegawa, M., Yamamoto, T. and Ihn, H. (2018), Diagnostic criteria, severity classification and guidelines of localized scleroderma. J Dermatol, 45: 755-780. https://doi.org/10.1111/1346-8138.14161