Published: August 16, 2022 (see history)
DOI: 10.7759/cureus.28058
Cite this article as: Magazzino O, Urbano T, Magnasco S (August 16, 2022) How to Treat Algodystrophy and Rheumatic Comorbidity in Myelofibrosis: Three Case Reports. Cureus 14(8): e28058. doi:10.7759/cureus.28058
Abstract
Algodystrophy or complex regional pain syndrome is a chronic pain condition characterized by hyperalgesia and allodynia. Patients with algodystrophy present an amplified and persistent activation of the innate immune system, with subsequent proliferation of keratinocytes and release of proinflammatory cytokines including interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α). Chronic inflammation and increased levels of cytokines are observed also in Ph-negative myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Chronic myeloid neoplasms are characterized by overproduction of one or more mature non-lymphoid cell lineages, with erythrocytosis, thrombocytosis, and/or myeloproliferation.
Three case reports described our experience in the treatment of algodystrophy and rheumatic conditions in patients with myelofibrosis; a literature search was also performed.
The first patient was a 58-year-old woman who suffered from chronic myeloproliferative neoplasm in myelofibrotic evolution, under treatment with ruxolitinib and pre-treated with hydroxyurea; she reported inflammatory pain, and swelling of the tibiotarsal joints bilaterally. She was treated with neridronate 2 mg/kg for four days and methotrexate 15 mg per os per week, achieving a clinical benefit. The second patient was a 63-year-old woman diagnosed with polycythemia vera evolving to myelofibrosis. She experienced pain and swelling of the left tibiotarsal joint and difficulty walking. A therapy with low-dose steroid per os and intramuscular clodronate was administered for four months, followed by methotrexate at 15 mg per week. After two months, tenosynovitis significantly improved, as supported by the evidence of improved bone edema of the left tibiotarsal joint revealed in the magnetic resonance imaging, and pain symptoms were clinically ameliorated. The third patient was a 70-year-old male patient affected by essential thrombocythemia with myelofibrotic evolution and a paraneoplastic polymyalgia rheumatica treated with steroids and currently in remission. The patient received ruxolitinib for about two years; after the first year of treatment, he experienced pain and swelling of the right tibiotarsal joint with difficulty in walking, with a consequent diagnosis of edema and tenosynovitis, as per algodystrophy. After consulting a rheumatologist, the patient received therapy with neridronate intramuscularly with clinical benefit.
As overlapping interactions and clinical manifestations between hematologic neoplasms and rheumatologic diseases exist, new clinical manifestations, such as algodystrophy, may emerge during myelofibrosis and need to be monitored in the long term by a multidisciplinary team.
Introduction
Algodystrophy is a chronic pain condition characterized by hyperalgesia and allodynia that can develop after extremity trauma, infection, or surgery [1]. The main features of algodystrophy are abnormal tissue response to injury, sensitization of the peripheral and central nervous systems, inflammatory changes, and autonomic dysregulation [2].
Focusing on the underlying inflammatory process, the clinical course of algodystrophy consists of an acute or warm phase, in which pro-inflammatory modulators are released, and a chronic or cold phase, where keratinocytes, fibroblasts, and osteocytes are activated [2].
During the acute phase, the release of pro-inflammatory cytokines, including interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) [3], triggers an immune cascade that results in histamine-induced vasodilation, causing the redness, swelling, pain, and warmth. These cytokines also activate the connective tissue, causing contractures [4], and alter bone metabolism by acting on osteoblasts and osteoclasts [5]. Then, during the chronic phase, rapid bone turnover, bone loss, and osteoporotic changes occur [5].
Some evidence in animal models and preclinical studies indicate that even autoimmunity plays a role in algodystrophy [6]. In mice treated with anti-CD20 and in mu-MT mice (lacking mature B cells), after fracture/cast immobilization, algodystrophy-like symptoms were less severe compared to wild-type mice that had undergone the same procedure; IgM deposition and complement activation were also observed in the skin and sciatic nerves of wild-type fracture/cast mice [7]. Furthermore, experiments using immunohistochemical techniques and fluorescence-assisted cell sorting (FACS) analysis identified sympathetic nervous system neurons as targets for autoantibodies in some patients with algodystrophy, with little evidence of such autoimmunity from patients with other types of peripheral neuropathy [8].
Algodystrophy shows a variable progression over time and early initiation of the therapy is mainly aimed at restoring limb functionality, decreasing pain, and improving the quality of life. To reach these goals, a multidisciplinary approach involving patient education, physical and occupational therapy, along with pharmacological and surgical interventions, is helpful.
Non-steroidal anti-inflammatory drugs (NSAID) and corticosteroids have been traditionally used to manage pain and inflammation of algodystrophy; furthermore, based on the positive results that emerged from small randomized clinical trials, bisphosphonates are also introduced in the treatment of algodystrophy [2]. Bisphosphonates can modulate inflammatory mediators, proliferation, and migration of bone marrow cells but their mechanism of action has not been accurately detailed. Over the past three decades, several case reports described positive results in controlling pain, local inflammation, functional disability, and improving the quality of life of patients, especially in patients with early disease [9]. A randomized trial compared the efficacy of neridronate versus placebo in patients with algodystrophy and showed a significant improvement in the indices of pain and quality of life [10]. A meta-analysis of four randomized clinical trials including a total of 181 patients showed a significant reduction of pain in patients with algodystrophy with bisphosphonates compared to placebo, demonstrating the efficacy and safety of bisphosphonates in the treatment of the disease [11].
As in algodystrophy, inflammation is considered one of the factors that contribute to the development and progression of Ph-negative myeloproliferative neoplasms (MPNs), including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF).
Indeed, current evidence suggests that MPNs are chronic inflammatory conditions in addition to neoplastic disorders and that both processes contribute to the clinical manifestations and pathogenesis of the disease [12]. The relationship between inflammation and myeloproliferation is supported by the evidence that increased levels of circulating cytokines and chemokines and the accumulation of reactive oxygen species in chronic inflammatory states can lead to genetic instability, which may promote the development and progression of neoplasms [12].
In MPNs, hyperactivation of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling due to the activating mutation V617F in the Janus kinase (JAK) 2 gene is frequently observed; in polycythemia vera and essential thrombocythemia, the JAK2 mutation can sustain a condition of chronic inflammation, explaining the associated constitutional symptoms, thrombosis, and premature atherosclerosis observed in patients with these disorders [12].
As the activating mutation V617F is a driver mutation in MPNs and is present in approximately 50% of patients with myelofibrosis, ruxolitinib, a potent oral inhibitor of JAK1/2, was tested in patients with myelofibrosis to examine the potential clinical benefit of JAK inhibition in this patients [13]. In a phase 1/2 trial, ruxolitinib showed clinical benefits associated with a marked diminution of levels of circulating inflammatory cytokines [13]. Therapeutic JAK2 inhibition with ruxolitinib reduced plasma levels of multiple cytokines in patients with myelofibrosis within the first month of treatment, without reverting them, however, to the low levels seen in healthy control plasmas [14]. Therefore, ruxolitinib can provide a partial, but incomplete, reduction of inflammatory pathophysiology in myelofibrosis. Other drugs currently used in patients with MPNs are hydroxyurea, anagrelide, and interferon [15].
Considering the high similarity in the inflammatory pathogenesis underlying both algodystrophy and MPNs, it is expected that clinical manifestations of rheumatological disorders are not uncommon during hematological malignancies.
In these case reports, we described our experience in the treatment of algodystrophy and rheumatic conditions in patients with myelofibrosis.
Case Presentation
Per the World Medical Association Declaration of Helsinki, all the data referring to the patients are published anonymously, without any details allowing re-identification of the patient. Informed consents were signed by the patient, as required by the law of the country.