Janus kinase inhibitor for multicentric reticulohistiocytosis, a new potential treatment

Multicentric reticulohistiocytosis (MRH) is a rare systemic disorder characterized by inflammatory histiocytic infiltrates, mainly affecting the synovium, skin, and subcutaneous tissues. In 2019, MRH was classified as the fourth subtype of systemic inflammatory multisystem conditions, associated with arthritis.1 MRH has only been reported in approximately 300 cases worldwide and does not appear to have a familial tendency. It is more commonly observed in women (female:male ratio of 3:1) with mean presentation age between 40 and 50 years old.2 Arthropathy is often rapidly progressive and can lead to destructive arthritis in 50% of MRH cases and flexion deformities in 14%.2, 3 Distal interphalangeal joints are the most frequently involved, and are one of the defining characteristics of MRH. Severe involvement of the interphalangeal joints can result in shortening and telescoping of digits, known as the “opera glass hand”. Although hands are most commonly affected, almost all the appendicular joints can be involved. Well-circumscribed marginal erosions and juxta-articular reabsorption are typical and can often lead to the widening of the joint space. Hence, radiography plays an important role in the diagnosis of MRH. Almost all cases of MRH have either preceding or simultaneous cutaneous lesions consisting of multiple nodules and papules ranging in size from a few millimeters to 2 cm. These lesions vary in color from dark reddish brown to flesh and typically appear on the face, hands, neck, and trunk, in decreasing frequency. Multiple nodules may merge into a bumpy cobblestone-like mass and periungual papules may produce a characteristic “coral bead” appearance. Sometimes MRH may be confused with dermatomyositis (DM). Differentiating MRH with features mimicking DM from a DM-MRH overlap syndrome is important for management decisions and comorbidity screening.4 The diagnosis of MRH relies on the analysis of biopsy specimens because of the absence of any distinct biomarker. Abnormal laboratory findings include anemia, hyperlipidemia, and elevation of acute-phase reactants in 30%–50% of cases.1 Tests are usually negative for rheumatoid factor, anti-cyclic citrullinated peptide, antinuclear antibodies, extractable nuclear antigens, and anti-neutrophil cytoplasmic antibody. Histopathology demonstrates numerous histiocytes and giant multinucleated cells with ground-glass–appearing eosinophilic cytoplasm.5 The histiocytes contain periodic acid-Schiff-positive material, with the presence of lysosomes and absence of Birbeck granules on electron microscopy. Immunohistochemical studies have identified cells in MRH as being positive for CD68, HAM56, Mac387, CD11b, CD11c, CD14, and CD15, consistent with a monocyte/macrophage origin. Additionally, CD1a and S100 stains are negative, indicating that the histiocytes are not Langerhans cells.2 As the etiology and pathogenesis of MRH remain unknown, treatment of MRH remains largely empirical. Analgesic or nonsteroidal anti-inflammatory drugs only offer symptomatic relief. Corticosteroids cannot usually induce complete remission, but they have a palliative effect. Many immunosuppressive or cytotoxic agents have been tried, such as methotrexate, leflunomide, azathioprine, cyclophosphamide, tacrolimus, thalidomide, hydroxychloroquine, and sulfasalazine.2 Of these, methotrexate is considered the most effective, but the development of intolerance is more common.6 Additionally, bisphosphonates seem to be effective by inducing necrosis and/or apoptosis of osteoclast-like macrophages.7 Although the drug combination might partially control arthritis symptoms and skin lesions, remission has been achieved infrequently. As controlled trials have not been performed for this rare disorder, it is difficult to know whether improvement is attributable to the therapy or to natural disease evolution. In recent years, several studies have demonstrated that proinflammatory cytokines such as interleukin-1 (IL-1), IL-1β, IL-2, IL-6, IL-8, IL-12, tumor necrosis factor-α (TNF-α), and monocyte chemoattractant protein-1, are present at high levels in both serum and involved tissues.8-11 Overexpression of these proinflammatory cytokines might be involved in the pathogenesis of MRH, so biological agents targeting these cytokines may be incorporated into our armamentarium to treat MRH. TNF-α antagonists (such as etanercept, infliximab, adalimumab, and golimumab), tocilizumab (IL-6 receptor inhibition), and anakinra (IL-1 receptor inhibition) have all shown promising results in improving both skin and articular lesions,6, 12-14 which have been used as a second-line option. In addition, rituximab has been reported as an effective treatment in one case.15 However, alternative small-molecule inhibitors of the cytokine signaling pathways are needed, as a result of the potential immunogenicity, unstable therapeutic effects, and inconvenient dosing regimens of biologics.16 Janus kinases (JAKs) are signaling proteins associated with the intracellular domain of receptor subunits for multiple cytokines. The JAK–signal transducer and activator of transcription (STAT) pathway regulates multiple biological processes including many aspects of both innate and adaptive immunity, hematopoiesis, and cell proliferation. The JAK family of tyrosine kinases comprises four isoforms (JAK1, JAK2, JAK3, and TYK2), each with specificity for a different set of cytokine receptors.16 JAK inhibitors (JAKi) are promising new drugs that have been clinically approved for the treatment of rheumatoid arthritis and ankylosing spondylitis.17, 18 To date, four successful cases of MRH treated with JAKi have been reported (Table 1).19-22 Interestingly, these reports cover three JAKi (tofacitinib, baricitinib, and upadacitinib) with different selectivity, indicating that JAKi may be a potential treatment option for MRH. The pan-JAKi tofacitinib, engineered to have greater selectivity towards JAK1 and JAK3, was verified in two MRH cases both with rapidly progressive severe joint symptoms.19, 22 The JAK1-selective upadacitinib was shown to work in a Canadian woman with a history of breast and ovarian carcinoma in situ,20 and the JAK1/JAK2 inhibitor baricitinib was demonstrated to be effective in reducing serious dermatomyositis-like skin lesions in a Chinese male patient.21 Patients treated with JAKi for less than 5 months have shown complete resolution without any clinical manifestations. All the patients have continued treatment without any adverse effects reported at the most recent follow up.22 The mechanism underlying the association of JAKi with MRH outcomes remains unclear, but may involve suppressing inflammation triggered by macrophages and reducing cytokine production. Each cytokine receptor recruits and employs a specific combination of JAKs, which may drive the development of T cells, regulate the growth of B cells, and activate natural killer cell proliferation. Differentiated T cells produce cytokines that contribute to various immune responses and are implicated in inflammatory and autoimmune diseases. JAKi targeting multiple cytokines simultaneously can suppress T-cell activation, thus reducing the production of inflammatory factors. Moreover, the success of biologic drugs validates a number of cytokine signaling pathways (IL-1 and IL-6), many of which signal through JAKs and STATs, as relevant drug targets for MRH.12, 13, 23 Although TNF does not induce immediate phosphorylation of STATs, JAKi can inhibit TNF-induced expression of several chemokines at the messenger RNA and protein levels, thereby limiting recruitment of T cells and other infiltrating leukocytes.24 Additionally, the intricate relationship between TNF-α and IL-6 creates redundant loops or signaling cycles, so blocking either of them can result in similar effects on inflammation.12 As TNF is of great importance in MRH pathology, as demonstrated by the success of anti-TNF therapies in MRH treatment, JAKi should be considered a promising treatment option by indirectly suppressing TNF function. Furthermore, JAKi has shown great potential in other histopathologically similar diseases, such as sarcoidosis and progressive nodular histiocytosis.25, 26 Moreover, while pan-JAKi will provide maximal efficacy, they carry the greatest risk of toxicity due to broad pathway suppression. In contrast, selective JAKi may decrease adverse effects and increase safety and efficacy.16, 27 More and more JAKi are currently in development, so it is important to consider the balance between benefits and risks of different agents in the future. In conclusion, although progress has been made in understanding the pathogenesis and treatment of MRH, further studies are needed to determine the frequency and pathogenicity of molecular alteration. In view of the rapid progression of arthritis mutilans, earlier diagnosis and aggressive therapy are crucial. More patients are needed to confirm the effectiveness of JAKi treatment; but we suggest JAKi as a promising treatment option for MRH, especially when conventional drugs have failed. Yuan Li: Data curation; Investigation; Validation; Visualization; Writing – original draft. Hanlin Yin: Conceptualization; Investigation; Project administration; Writing – review & editing. Le Zhang: Writing – review & editing; Liangjing Lu: Conceptualization; Project administration; Supervision; Writing – review & editing. The authors thank the Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine. The authors declare they have no competing interests. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

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