Severe but reversible pulmonary hypertension in scleromyxedema and multiple myeloma: a case report

Scleromyxedema (papular mucinosis, generalized lichen myxedematous, Arndt-Gordon disease) is a rare, chronic, progressive disorder characterized by skin lesions with mucinous material deposition, fibrosis, increased population of fibroblasts, and high levels of immunoglobulins (monoclonal gammopathy of unknown significance [MGUS]) in serum without a corresponding thyroid abnormality [1‐11]. In a subset of cases described by Rongioletti et al., immune cell infiltrates may also be present in skin lesions in a “granuloma annulare-like pattern” [7]. Scleromyxedema is a multi-organ disorder that can involve the nervous system, lungs, heart, kidneys, esophagus, larynx, eyes, muscles, bone marrow, and skin [2‐11]. Death can occur due to organ involvement or evolution into a blood malignancy or other cancer [2‐4, 6, 8, 10‐19]. In a 2013 retrospective study of 30 scleromyxedema cases, two patients died from Hodgkin lymphoma or myeloid leukemia at 22 months and 11 years post-scleromyxedema diagnosis, respectively, without undergoing melphalan treatment (a chemotherapeutic agent associated with development of hematological malignancies) [2, 3, 6, 8, 12]. Treatment generally involves modulating the immune system, decreasing the population of plasma cells, and/or improving dermatological manifestations of the disease; pharmacological and surgical treatments include intravenous immunoglobulin (IVIG), thalidomide/thalidomide derivative lealidomide, systemic glucocorticoids, melphalan, bortezomib plus dexamethasone, and autologous stem cell transplantation among others [2‐6, 8‐14, 16‐41].

As a dermatological condition with disease characteristics similar to scleroderma, scleromyxedema is generally classified as a connective tissue disorder with associated immune system/inflammatory responses, but due to the abnormal amounts of monoclonal immunoglobulin produced (paraproteinemia) and associated abnormal plasma cell populations, scleromyxedema is also considered a paraneoplastic and hematologic disorder [1‐11, 36]. In these contexts, many scleromyxedema-associated syndromes can develop, including pulmonary hypertension (PH), myeloproliferative neoplasms (MPN), leukemia/lymphoma, and multiple myeloma [1, 6, 8‐22, 24‐27, 29, 31‐33, 35‐37, 39‐41]. PH, defined by a mean pulmonary arterial pressure of ≥25 mmHg at rest, can also occur in patients with MPN and other paraneoplastic conditions, and it is demonstrated in the medical literature that PH symptoms improve in response to treatment when the underlying MPN is targeted [25, 42‐63]. Therefore, prescribing treatment regimens that target the overlapping pathophysiological characteristics of these associated conditions may simultaneously improve symptomology in patients with multi-system scleromyxedema [2, 13, 17, 19‐22, 24‐26, 36].

In this case report, we describe the diagnosis, treatment, and progression of PH in a patient who had scleromyxedema and developed multiple myeloma refractory to triple PH treatment that resolved with a combination treatment of bortezomib, cyclophosphamide, and dexamethasone. We propose that combination therapy with the anti-neoplastic agent bortezomib is an important adjuvant therapy to reverse vasodilator resistant PH in patients with scleromyxedema and plasma cell dyscrasias.

Pulmonary hypertension has occurred in association with various hematologic malignancies, particularly those with underlying plasma cell dyscrasias [25, 42‐63]. The first case of reversible PH in response to antineoplastic treatment for a scleromyxedema-like condition and hematological malignancy was described by Yaqub et al. in 2004, and in 2015, Feyereisn described the diagnosis, treatment, and outcome of four cases of reversible PH in the setting of plasma cell dyscrasias one of which had scleromyxedema [24, 25]. The overall frequency and spectrum of PH in this setting remains largely undefined.

In our patient with scleromyxedema, multiple anti-neoplastic and immunomodulatory treatment regimens were used to alleviate dermatological and cardiopulmonary symptoms. Immunomodulatory treatments like IVIG, glucocorticoids, and hydroxychloroquine were administered over the entire course of the disease but were unable to produce a complete remission of skin and cardiopulmonary symptoms. Administration of anti-neoplastic agents like thalidomide and bortezomib led to decreased paraprotein levels on multiple occasions and corresponded to improved pulmonary dynamics in a manner similar to previously published cases [24, 25, 27, 60]. Close monitoring and treatment alteration was necessary to prevent unanticipated clinical events. Thalidomide or thalidomide derivatives were used at two points over the course of this patient’s history but were halted due to development of neuropathy and other adverse side effects. Although anti-neoplastic/chemotherapeutic agents can be associated with the development of PH, pulmonary injury, and hematological malignancies, we do not believe this occurred based on the temporal progression of scleromyxedema from a localized cutaneous condition to a generalized disease with multiple phenotypes over a period of 9 years [2‐4, 6, 8, 10‐12, 47, 53, 64‐80]. Furthermore, PH developed 2 years after thalidomide treatment was stopped, and cardiopulmonary symptoms for the most part resolved in response to multiple myeloma treatment. Despite a partial therapeutic response with respect to abnormal plasma cell populations and IgG production, this patient experienced excellent recovery of cardiopulmonary function when on anti-neoplastic treatment regimens. Thus, a complete remission of scleromyxedema and associated plasma cell dyscrasia and paraprotein levels does not appear to be necessary to obtain a significant improvement in PH symptoms.

Although the physiopathology of PH development in response to plasma cell dyscrasias has not been fully elucidated, the reversibility of hemodynamics in response to treatment with chemotherapeutic and immunomodulatory agents offers hope for PAH patients [24, 25, 27, 42, 43, 45, 50, 53, 57‐60, 62, 63, 81‐103]. Improvements in hematopoietic cell populations, paraprotein levels, and hemodynamic functions in our patient and other cases of reversible PH suggest that abnormal plasma cell populations play a central role in the development of PH [24, 25, 27, 43, 45, 50, 53, 57‐60, 62, 63, 81, 84‐86, 91]. Furthermore, patients with scleromyxedema and related conditions who received treatments traditionally used for multiple myeloma have exhibited decreases in IgG and paraprotein levels that co-occurred with clinical improvements, as in our patient [17, 20‐25, 31, 35, 60, 61]. This may also indicate a direct link between decreased paraprotein levels and hemodynamic improvements by way of improved hyperviscosity and associated microvascular dysfunction [8]. However, detectable paraprotein levels are not always present nor correspond to the severity, progression, and response of scleromyxedema to standard treatments for this condition; therefore, the relative contribution of scleromyxedema progression and paraprotein levels to PH development is unclear [3, 5, 6, 8, 9, 13, 14, 16‐18, 20‐25, 31, 35, 60, 61]. Other pathobiological mechanisms invoked in the development of scleromyxedema and/or associated with plasma cell dyscrasias may also contribute to the development of PAH. These include increased secretion and expression of cytokines, dysregulation of immune system activities, and/or abnormal pulmonary fibroblasts, mucin deposition in the pulmonary vasculature, and direct invasion of the pulmonary vasculature by abnormal plasma cells [2‐4, 8, 11, 14‐16, 18, 27, 29, 31‐38, 41, 57, 62, 63, 81, 86, 87, 96, 104‐111]. Alternatively, a direct effect of chemotherapeutic agents on the pulmonary vasculature and associated abnormal humoral milieus may also have played a role in this reversibility. Due to the multifaceted nature of PH development and reversibility in response to treatment, it is also possible that a multi-hit model, as in idiopathic pulmonary arterial hypertension (IPAH), is plausible [106]. Regardless of the underlying etiology, patients with concurrent PH and MPN or vice versa have demonstrated hemodynamic improvements in response to chemotherapeutic agents; thus, patients with vasodilator-resistant PH may derive benefit from cancer treatments [25, 27, 42‐63].

Evidence for a cancer-like pathology and direct effects of immunosuppressive and anti-proliferative agents on PH development and progression is present in case reports for patients with PAH [24, 25, 42, 43, 45‐55, 57, 58, 60‐63, 76, 81, 85‐87, 90‐96, 105‐107, 110‐113]. According to Price et al., “Pathologic specimens from patients with PAH demonstrate an accumulation of perivascular inflammatory cells,” and laboratory analysis of serum from patients with PAH revealed increased levels of cytokines, chemokines as well as autoantibodies to endothelial cells and fibroblasts [105, 108, 109]. In parallel to those abnormalities, the pulmonary vascular cells of patients with PAH exhibit many features of cancerous cells from dysregulated metabolism to increased cell proliferation and resistance to apoptosis [106, 109]. These observations combined with the occurrence of PAH in various connective tissue diseases support the role of inflammation, autoimmunity, and a neoplastic-like dysregulation at the center of the pathogenesis of PAH [105‐107, 110‐113]. This model could provide a mechanistic explanation for the hemodynamic improvements noted in our patient and in many patients with PAH in response to immunosuppressive and anti-proliferative agents [24, 25, 27, 42‐63]. The following paragraphs provide a description of currently used agents for multiple myeloma and/or scleromyxedema that have proven effective for patients with PAH.

Glucocorticoids have an inhibitory effect on multiple types of immune cells and produce broad anti-inflammatory and immunosuppressive effects [114]. Glucocorticoids have been used as a treatment for scleromyxedema with positive effects reported in single case reports, and its efficacy against collagen disease-associated PAH is well known [31‐35, 84, 88‐90, 112‐114]. Glucocorticoids are also used as a first line therapy for multiple myeloma in combination with other chemotherapy regimens in patients ineligible for autologous stem cell transplantation [115]. Improvements post-prednisolone treatment have been noted in adult and pediatric patients with iPAH as well as in monocrotaline-induced pulmonary arterial hypertension in rodents [88‐90, 96, 97].

Rituximab is an FDA-approved chimeric anti-CD20 monoclonal antibody for various malignancies and autoimmune disorders [116]. It exerts its immunosuppressive and anti-proliferative effects through antibody- and complement-mediated dependent cellular toxicity and apoptosis and has been used anecdotally for mixed connective tissue disorders [91, 112, 116]. Previously published case reports demonstrated improvements in collagen vascular disease-associated PAH in response to rituximab treatment, and a large randomized placebo controlled clinical trial of rituximab for the treatment of scleroderma-associated PAH is currently underway (ClinicalTrials.​gov identifier NCT01086540) [92, 93]. In a presumed case of iPAH, rituximab co-treatment with chemotherapy for lymphoma lead to symptom resolution, and PAH in the setting of Castleman lymphoma was also noted to respond to rituximab [63, 85]. However, in two instances, rituximab use was associated with the development of PH [79, 80].

Plasma exchange or plasmapheresis is an automated technique that permits the selective therapeutic exchange of patient plasma with another fluid. Plasma exchange has been suggested as a treatment for scleromyxedema and was noted to improve PAH in association with various connective tissue diseases [37, 38, 86]. Immunoadsorption (IA), another extracorporeal automated technique to selectively remove immunoglobulins from the plasma of PAH patients via high affinity absorbers, is a promising treatment for iPAH; in 5 patients with severe iPAH awaiting transplant, IA improved symptoms associated with iPAH [94]. IA as an add-on to targeted medical therapy also led to improvements in mean PVR and CI in 10 patients with iPAH though these hemodynamic improvements did not correlate to substantial improvements in the 6 mn walk test [95].

Bortezomib is a proteasome inhibitor that is FDA-approved for the treatment of multiple myeloma [117, 118]. In the medical literature, patients with multiple myeloma and PH can experience reversal of PH symptoms with bortezomib treatment, although adverse pulmonary effects have also been reported in association with this drug [25, 64‐71, 73, 75, 76]. Steroid co-treatments can prevent bortezomib-induced lung injury, though additional studies are needed to assess both the adverse pulmonary side effects as well as the protective effect of an adjuvant steroid regimen for bortezomib treatment [64‐71, 73, 75, 76]. In animal models of pulmonary disease, bortezomib treatment reverses adverse cardiopulmonary effects and can improve survival post-monocrotaline-induced PH/PAH [98‐103]. In a mouse model of hypoxia-induced PH, bortezomib treatment prevented an increase in right ventricular systolic pressure, ratio of right ventricular weight to left ventricular weight and septum (right ventricular hypertrophy index), percent medial wall thickness, and muscularization of pulmonary vessels and inhibited vascular smooth muscle proliferation [98]. A similar treatment effect was observed in rats with monocrotaline- or left-to-right shunt-induced PAH, and bortezomib treatment also enhanced survival in monocrotaline-injected rats compared to monocrotaline-injected rats without bortezomib treatment [98‐102]. In a chronic hypoxia-induced PAH rat model, Ibrahim and colleagues noted that anti-tumor agents, specifically bortezomib, MG-132, and daunorubicin, decreased pulmonary vessel thickness and, in the case of daunorubicin and MG-132, improved pulmonary response to vasodilator treatment [103]. Together, these results suggest that proteasome inhibitors alone or in combination with vasodilators could potentially prevent and/or reverse PAH-induced pulmonary vessel remodeling and hemodynamic response in PAH afflicted patients [98‐103].

Regardless of the agent selected, it is clear from our and previous cases that PH/PAH can be improved by the addition of anti-neoplastic agents to the overall treatment regimen of patients with conditions that produce plasma cell dyscrasias, abnormal protein levels, and increased extracellular matrix deposition [24, 25, 27, 43, 45, 50, 53, 57‐60, 62, 63, 81‐103]. However, these therapies can produce adverse side effects that may potentially limit the number and type of treatments available for PH, multiple myeloma, and other conditions associated with multi-system scleromyxedema [2‐4, 6, 8, 10‐12, 47, 53, 64‐80]. Careful monitoring is necessary to mitigate adverse treatment effects in this patient population.

Although bortezomib and cyclophosphamide are generally used as second- and third-line treatments for scleromyxedema and related cutaneous mucinoses, these agents may be an effective primary therapy for these conditions in combination with glucocorticoids and/or proteasome inhibitors [4, 6, 8, 10, 13, 14, 16‐18, 22‐24, 26, 27, 30, 69, 87] especially in the presence of plasma cell dyscrasia-associated PAH. Treatment of our patient’s underlying plasma cell abnormality with a combination treatment of cyclophosphamide, bortezomib, and dexamethasone not only reduced the population of abnormal plasma cells in the bone marrow but also improved the dermatological, cardiopulmonary, and paraprotein effects of scleromyxedema and multiple myeloma-induced PH as well similar to a few other previously reported cases [24, 25, 27, 60]. Therefore, a combination regimen of cyclophosphamide, dexamethasone, and bortezomib may be an effective multi-target treatment for patients with PH refractory to vasodilator treatment, in the setting of plasma cell dyscrasias and elevated paraprotein levels. Additional work is necessary to understand the physiology of chemotherapeutic agents for PAH-associated plasma cell dyscrasias and develop treatment regimens to maximize clinical response with minimal side effects.