Treatment of a Complex Case of Scleromyxedema Using a Novel Intravenous Immunoglobulin Preparation

Scleromyxedema is a rare, severe cutaneous mucinosis characterized by the abnormal accumulation of mucin in the skin [1‒3]. The diagnosis of scleromyxedema relies on the following criteria as proposed by Rongioletti: widespread papular and sclerodermiform eruptions, a histological triad characterized by mucin deposits, fibroblast proliferation, and fibrosis as well as the presence of monoclonal gammopathy and the absence of thyroid disease [1, 4].

Regarding skin manifestations, papules typically emerge on the back of the hands, the extensor sides of the arms, the upper trunk/back, the face, or the axillae. The widespread dissemination of papules, occasionally observed on sclerosing skin, serves as an indicative feature suggestive of scleromyxedema [1, 4]. The “donut sign,” which manifests as a depression with a raised margin over the proximal interphalangeal joints of the fingers, is often observed [1]. Another manifestation on the face involves the development of thickened, rough skin with prominent folds, commonly referred to as facies leonina [1, 4]. Sclerodactyly, characterized by skin tightening and thickening on the fingers, along with areas of mild erythema, may be observed as well as sparse hair growth. Some patients may further experience intermittent itching. Arising problems may include the formation of contractures restricting joint movement of the extremities and stiffness of facial muscles impairing facial expressions and mouth opening [1]. The typical histological characteristics of scleromyxedema encompass mucin accumulation among collagen fibers in the upper and middle reticular dermis, an augmented population of fibroblasts featuring large, star-shaped nuclei, and collagen fiber thickening [1, 5].

Scleromyxedema is associated with monoclonal gammopathy of undetermined significance (MGUS) in about 90% of patients [1, 4]. In over 80% of cases, monoclonal IgG (usually lambda) is found, less frequent IgM (kappa), IgA (kappa), or IgA (lambda) [1].

Untreated scleromyxedema follows an unpredictable course, typically progressing over several years [1, 4]. Effective treatment options with ongoing benefits and acceptable side effects include intravenous immunoglobulin (IVIg) therapy. This is also a first-line recommendation of current European guidelines. Other approaches like lenalidomide, bortezomib, and dexamethasone have also been evaluated [1, 3, 4]. IVIgs are therapeutic formulations containing human antibodies derived from thousands of healthy donors. These preparations undergo a complex manufacturing process to meet the high quality and safety standards, such as preserving the structural and functional integrity of IgG antibodies with a purity of at least 95%, integration of highly effective and validated virus reduction steps as well as epidemiological screening and virological testing of both donor blood and pooled plasma [6‒8]. Healthy human serum is predominantly composed of IgG at approximately 75% [6]. Special measures are taken to minimize IgA levels in IVIgs, as high concentrations can trigger severe reactions in individuals with selective IgA deficiency [6]. The commercially available IVIg formulations differ with regard to the choice of stabilizing agent, such as sucrose, glucose, maltose, d-sorbitol, l-proline, or glycine, whereby the use of sugar-free solutions is recommended for patients at risk, e.g., with preexisting renal insufficiency, as formulations containing sucrose in particular have been associated with renal dysfunction and acute renal failure [9, 10]. In scleromyxedema, the standard dosage regimen for high-dose IVIg typically involves administering 1–2 g per kilogram of body weight (g/kgbw) over a span of 2 to 5 days, repeated every 4 weeks [6].

Here, we report on a 57-year-old patient who presented with pruritic erythematous plaques on the sides of the fingers and toes in 2008 (Fig. 1). From 2010, skin-colored papules emerged on the entire integument, including the face (Fig. 2a). The CARE Checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000540519).

Concurrently, the patient was diagnosed with MGUS, specifically IgG kappa type, in 2011. He developed renal insufficiency necessitating hemodialysis in January 2012, attributed to histologically evident nephrosclerosis. Since then, the patient underwent hemodialysis three times per week and has unfortunately required multiple shunt revisions due to decreased flow. His renal condition further led to poorly controlled hypertension and consecutive loss of visual function due to hypertensive retinopathy.

Upon initial assessment at our dermatology department in August 2012, significant skin induration with a notable restriction of mouth and eye opening, eyelash loss, and ectropion was observed (Fig. 2). Based on clinical and histological findings, diagnosis of scleromyxedema was confirmed. The patient’s skin condition failed to respond to topical steroids and PUVA treatment. Consequently, immunosuppressive therapy with prednisolone 100 mg/day was initiated, but turned out to be ineffective.

Given the limited options for additional immunosuppression in the context of dialysis-dependent renal insufficiency, high-dose IVIg was the treatment of choice. Due to preexisting renal insufficiency, a sugar-free IVIg preparation (Intratect^® 100 g/L with a dose of 2 g/kgbw distributed over 2 days every 4 weeks) was chosen and initiated in February 2013 (Fig. 2b). Concerning further treatment, several factors had to be considered. Since high-dose IVIg therapy is associated with a relative increase in blood viscosity, frequently leading to headaches and other adverse effects, both the daily dose (distribution of the dose over 3–5 consecutive days) and the infusion rate should be reduced to the lowest feasible level in patients with renal impairment or those prone to thromboembolic adverse reactions [10, 11]. Notably, in the herein presented case, the scheduling of IVIg intervals was particularly restricted due to the fixed dialysis intervals and the psychological strain of continuous hospitalization endured by the patient. Administering IVIg doses over more than 2 days was not possible due to the 3-days-a-week dialysis regimen and was also refused by the patient. Nonetheless, the infusion rate was reduced to the practical minimum of 1.6 mL/kgbwh. Fortunately, IVIg quickly resulted in a notable improvement of the patient’s skin and overall well-being.

Further on, the patient experienced syncopal episodes and was diagnosed with AV-block III, subsequently undergoing pacemaker implantation. The development of multiple basal cell carcinomas and other rare skin tumors such as trichoepitheliomas required multiple surgical interventions. Hence, kidney transplantation due to renal insufficiency was precluded. Due to persistent disease activity, progression of skin lesions and elevated intraocular pressure IVIg Intratect^® intervals were reduced to 2 g/kgbw over 2 days every 3 weeks in March 2020, resulting in disease stabilization (Fig. 2a–c).

Nevertheless, the patient reported headaches, lethargy, and fatigue following Intratect^® administration lasting up to 1 week. Experiencing fever, chills, and malaise for 3 days following each cycle of Intratect^® had the most pronounced impact on quality of life. Hence, in September 2023, the patient was transitioned to the novel sugar-free IVIg preparation Yimmugo^® (Yimmugo 100 g/L; Biotest AG; 2 g/kgbw distributed over 2 days every 3 weeks). After the first infusions, the patient reported fewer side effects with Yimmugo^® compared to Intratect^®, experiencing reduced fatigue and fewer headaches, resulting in increased productivity following IVIg administration. This was accompanied by ongoing clinical remission of scleromyxedema lesions. In November 2023, shunt thrombosis was detected during dialysis, which led to the initiation of anticoagulation therapy without the necessity of surgical intervention thus far.

Our case reports on a patient with a severe manifestation of scleromyxedema presenting with extensive skin involvement. In addition to the skin condition, the patient is affected with MGUS, having resulted in renal insufficiency and subsequent hemodialysis. The only treatment that improved disease progression with tolerable side effects was high-dose IVIg therapy. Initially, the patient received the sugar-free IVIg preparation Intratect^®. At 4-week IVIg cycles, skin thickening progressed and eye opening was still impaired, which necessitated a reduction in intervals to every 3 weeks in order to stabilize disease (Fig. 2). Although lacking scientific evidence, antibodies administered via IVIg should not be removed by dialysis. However, heightened disease activity may alter metabolism and accelerate antibody degradation, potentially necessitating a reduction in the IVIg therapy interval from 4 to 3 weeks like in our case.

Side effects reported by the patient during therapy with Intratect^® are frequently associated with IVIg and are usually mild and temporary, similar to other common side effects such as flushing or feelings of warmth [6, 10, 11]. Rare and severe adverse events of IVIg may involve renal impairment, thrombosis, arrhythmia, aseptic meningitis, hemolytic anemia, and transfusion-related acute lung injury [6, 12]. Due to changes of blood viscosity, adverse events may occur more frequently, especially in patients on high-dose IVIg therapy. Special precautions should be taken in patients at risk of cardiovascular and thromboembolic events and in patients with renal impairment – all of these factors applied to the here presented patient. General recommendations for safe use of IVIg in high-risk patients include dose and infusion rate reduction, premedication, and hydration [9‒11]. Unfortunately, most of these recommendations could only be implemented to a limited extent in this case. We therefore decided to switch the patient to another sugar-free IVIg product, Yimmugo^® 100 g/L, as it is presumed that certain side effects are related to specific IVIg formulations and individual tolerability [10, 11, 13]. As anticipated, the patient noted enhanced well-being after the first Yimmugo^® infusion and a shorter period of fatigue and headache. He was satisfied with the switch of therapy.

Regrettably, after three cycles of Yimmugo^®, the patient experienced shunt thrombosis. This complication is probably not directly related to Yimmugo^® itself, as earlier functional tests have unequivocally demonstrated the absence of procoagulant activity in this IVIg product [8]. It seems more likely that shunt thrombosis was related to IVIg therapy in general than to a specific formulation [11, 12]. Besides, the patient had previously suffered shunt thromboses, indicating an individual predisposition related to his general condition, as patients with a history of vascular disease or thrombotic episodes generally have an increased risk of thrombotic events [10, 11].

Since IVIg therapy with Intratect^® resulted in adverse effects which impaired the patient’s quality of life, aggravating the challenges posed by the disease itself, switching to an alternative IVIg formulation, namely, Yimmugo^®, was undertaken. Initial observations suggested an improvement in quality of life and a reduction in side effects. Continuous monitoring is imperative to definitively assess efficacy and tolerability. Since there is still no curative therapy for scleromyxedema, it is of utmost interest that treatment controls disease progression while preserving the patient’s quality of life. Here, high-dose IVIg therapy is a promising treatment approach [1, 2]. Prospective and comparative studies are essential to validate the efficacy and safety of IVIg for this uncommon yet potentially life-threatening disorder.

Written informed consent was obtained from the patient for publication of this case report and all accompanying images. Ethical approval was not required for this case report, in accordance with local and national guidelines.

Alexander Enk received advisory board honoraria, consultancy fees, and support for this publication from Biotest AG. The other authors state no conflict of interest related to the study.

This study was not supported by any sponsor or funder.

A.S. Vollmer and N. Wiedenmayer had substantial contributions to the acquisition, analysis, and interpretation of data for the work, in drafting the work, and in the final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. J.K. Winkler and A. Enk had substantial contributions to the conception of the work and interpretation of data, to critically reviewing it for important intellectual content, and to final approval of the version to be published and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Julia K. Winkler and Alexander H. Enk contributed equally to this work.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.