Abstract
Multicentric reticulohistiocytosis (MRH) is a rare, multisystemic non-Langerhans cell histiocytosis characterized by skin and articular involvement, and rarely involves various other organs. There are no specific laboratory findings for MRH. Diagnosis is based on clinical findings and skin or synovial biopsy results. There is currently no consensus for the treatment of MRH. Here, we review the differential diagnosis and treatment options of MRH from the rheumatologist’s perspective. We also report an index case of MRH associated with Sjögren’s syndrome and pulmonary embolism.
Introduction
Multicentric reticulohistiocytosis (MRH) is a rare, multisystem non-Langerhans cell histiocytosis of unknown etiology and characterized by symmetric polyarthritis and papulonodular skin lesions.
The majority of patients present with joint symptoms. The arthritis tends to be symmetrical, mainly involving the distal interphalangeal (DIP) joints, wrists, elbows, shoulders, hips, knees, and feet, and can lead to joint destruction and deformities known as arthritis mutilans . Typical skin manifestations consist of reddish-brown papules or nodules, mainly involving the face, hands, and forearm. Mucosal lesions are also present in about half of the patients. In addition to the skin and joints, involvement of the muscles, bones, lungs, heart, salivary glands, thyroid glands, and kidney has been described .
A literature search revealed more than 200 case reports of MRH, which occurs predominantly in whites. Women are affected 3 times more often than men . The onset of MRH is usually in the fourth decade of life, although it has been reported both in children and elderly people . There are no definitive diagnostic laboratory tests for MRH. Autoantibody tests such as rheumatoid factor (RF), anticyclic citrullinated peptide (anti-CCP), and antinuclear antibody (ANA) are usually negative. The definitive diagnosis is based on histologic findings of the affected tissue consisting of multinucleated giant cells with ground-glass appearance of the eosinophilic cytoplasm with positivity for several monocytic and histiocytic markers .
MRH has been reported in association with several malignant conditions including hematologic malignancies such as lymphoma and leukemia; cancers of the lung, ovaries, endometrium, breast, and colon; and mesothelioma, sarcoma, and melanoma . MRH may also be associated with systemic autoimmune diseases including systemic lupus erythematosus, rheumatoid arthritis (RA), and Sjögren’s syndrome (SS) and other conditions such as hypothyroidism, diabetes, and pregnancy .
Currently, there is no consensus for the optimum treatment of MRH, and spontaneous remission within 5–10 years of diagnosis is reported as a usual outcome.
In this review, we report an index case of MRH in association with SS to reflect the rheumatologist’s perspective.
Index case
A 64-year-old man presented with pain, swelling, and tenderness in his fingers, wrists, elbows, knees, and shoulders. Further questioning revealed that the patient had symptoms of dry eyes and mouth for 1 year. Subsequently, he had developed multiple skin nodules on his forearm and an erythematous, V-shaped eruption that involved the chest. Six months before his presentation to our clinic, he was evaluated in another hospital with gradual shortness of breath and chest pain. A computed tomographic (CT) scan of the thorax revealed right-sided pleural effusion, pulmonary embolism in the segmental arteries of the right lower lobe, and bilateral subcentimetric pulmonary nodules. He was diagnosed to have seronegative arthritis and pulmonary embolism for which he received prednisolone and warfarin before his presentation to our clinic. On physical examination, erythema, swelling, and tenderness were noted on the proximal interphalangeal and metacarpophalangeal joints, wrists, and shoulders. Multiple reddish-brown papulonodular lesions were observed on his nose, ear, forearm, and chest ( Fig. 1 ). The remaining physical examination findings were normal. The initial clinical diagnosis was dermatomyositis with SS and possible antiphospholipid syndrome.
Laboratory investigations showed hemoglobin levels of 11 g/dL, C-reactive protein (CRP) level of 8 mg/L, and erythrocyte sedimentation rate (ESR) of 70 mm/h. Electrolytes, kidney and liver function tests, and creatine kinase levels were normal. Further analysis revealed positive anti-Ro (SS-A) and anti-La (SS-B) autoantibodies and Schirmer’s test (<5 mm). Tests for ANA, anti-dsDNA, anti-Smith, anticentromere, anti-ribonucleoprotein (anti-RNP), anti-Jo1, anti neutrophil cytoplasmic antibodies (ANCA), cryoglobulins, RF, anti-CCP, lupus anticoagulant, anticardiolipin antibodies, anti-β 2 -glycoprotein I antibodies, HbsAg, anti-Hepatitis C virus (HCV), factor V Leiden mutation, and G20210A mutation of the prothrombin gene were negative. The results of protein C and protein S, antithrombin level, C3, and C4 were normal. The minor salivary gland biopsy revealed a diffuse lymphocytic infiltration. Plain X-rays of the joints were normal. Histopathologic examination of the biopsy specimen obtained from the nasal nodules and the second finger is shown in Fig. 2 . To further evaluate the subcentimetric pulmonary nodules seen on the chest tomography, further examination with a positron emission tomography–CT (PET–CT) scan did not show any lesions suspicious for malignancy.
The patient’s clinical findings and histopathology were consistent with the diagnosis of MRH associated with SS. Treatment was started with oral methotrexate (MTX) 10 mg per week, hydroxychloroquine 400 mg per day, and methylprednisolone 32 mg per day. The polyarthritis resolved within 1 month. The erythema on the V of the chest and papulonodular lesions gradually decreased over the 6 months following initiation of therapy, and corticosteroid dosage was gradually tapered.
Index case
A 64-year-old man presented with pain, swelling, and tenderness in his fingers, wrists, elbows, knees, and shoulders. Further questioning revealed that the patient had symptoms of dry eyes and mouth for 1 year. Subsequently, he had developed multiple skin nodules on his forearm and an erythematous, V-shaped eruption that involved the chest. Six months before his presentation to our clinic, he was evaluated in another hospital with gradual shortness of breath and chest pain. A computed tomographic (CT) scan of the thorax revealed right-sided pleural effusion, pulmonary embolism in the segmental arteries of the right lower lobe, and bilateral subcentimetric pulmonary nodules. He was diagnosed to have seronegative arthritis and pulmonary embolism for which he received prednisolone and warfarin before his presentation to our clinic. On physical examination, erythema, swelling, and tenderness were noted on the proximal interphalangeal and metacarpophalangeal joints, wrists, and shoulders. Multiple reddish-brown papulonodular lesions were observed on his nose, ear, forearm, and chest ( Fig. 1 ). The remaining physical examination findings were normal. The initial clinical diagnosis was dermatomyositis with SS and possible antiphospholipid syndrome.
Laboratory investigations showed hemoglobin levels of 11 g/dL, C-reactive protein (CRP) level of 8 mg/L, and erythrocyte sedimentation rate (ESR) of 70 mm/h. Electrolytes, kidney and liver function tests, and creatine kinase levels were normal. Further analysis revealed positive anti-Ro (SS-A) and anti-La (SS-B) autoantibodies and Schirmer’s test (<5 mm). Tests for ANA, anti-dsDNA, anti-Smith, anticentromere, anti-ribonucleoprotein (anti-RNP), anti-Jo1, anti neutrophil cytoplasmic antibodies (ANCA), cryoglobulins, RF, anti-CCP, lupus anticoagulant, anticardiolipin antibodies, anti-β 2 -glycoprotein I antibodies, HbsAg, anti-Hepatitis C virus (HCV), factor V Leiden mutation, and G20210A mutation of the prothrombin gene were negative. The results of protein C and protein S, antithrombin level, C3, and C4 were normal. The minor salivary gland biopsy revealed a diffuse lymphocytic infiltration. Plain X-rays of the joints were normal. Histopathologic examination of the biopsy specimen obtained from the nasal nodules and the second finger is shown in Fig. 2 . To further evaluate the subcentimetric pulmonary nodules seen on the chest tomography, further examination with a positron emission tomography–CT (PET–CT) scan did not show any lesions suspicious for malignancy.
The patient’s clinical findings and histopathology were consistent with the diagnosis of MRH associated with SS. Treatment was started with oral methotrexate (MTX) 10 mg per week, hydroxychloroquine 400 mg per day, and methylprednisolone 32 mg per day. The polyarthritis resolved within 1 month. The erythema on the V of the chest and papulonodular lesions gradually decreased over the 6 months following initiation of therapy, and corticosteroid dosage was gradually tapered.
Basic clinical aspects of MRH
MRH is a non-Langerhans histiocytosis in which symmetric polyarthritis and multiple papulonodular skin lesions are the most common initial symptoms. Typical skin lesions usually follow articular involvement after an average of 3 years in majority of the patients . Rarely, these patients experience symptoms of other organ system involvements.
Arthritis associated with MRH
Musculoskeletal involvement occurs as an initial symptom in almost 40% of cases. Arthritis associated with MRH tends to be symmetrical and erosive in a polyarticular pattern mimicking RA. Shoulders, wrists, elbows, hips, knees, ankles, and feet are the most commonly affected joints, and axial involvement has been reported rarely in MRH . Unlike RA, DIP joints are frequently affected in MRH. In the absence of effective treatment, the destruction of the proximal interphalangeal and DIP joint may result in arthritis mutilans and “opera-glass hand” . There are reports of destructive arthropathy that necessitated arthrodesis of the metacarpophalangeal joints and bilateral hip replacement .
Skin manifestations
Cutaneous involvement occurs initially in 18% of patients, and more commonly follows the involvement of the joint . The typical cutaneous manifestations of MRH are multiple reddish-brown to flesh-colored papulonodular skin lesions varying from 1–2 mm to 1 cm in diameter. Atypical skin lesions include macular photodistributed erythema, periungual telangiectasia, and xanthelasma-like lesions . Skin lesions may occur on any surface of the body. The most common sites are the dorsum of the hands, fingers, and face. Periungual papulonodular lesions mimicking “coral beads” constitute a characteristic sign of MRH . These lesions may be isolated or in groups and they are usually asymptomatic. Patients may complain of pruritus, while pain is usually absent. Patients may present with photodistributed macular eruptions on the face, the V of the neck, or the forearms. MRH might clinically mimic dermatomyositis as suggested previously . Mucosal surface of the mouth is involved in more than half of the cases. Skin and mucosal findings may regress spontaneously or with therapy . Ultraviolet-light-induced Koebner phenomenon may contribute to the development of the skin lesions of MRH . Patients with MRH may also show nail changes, including atrophy, longitudinal ridging, brittleness, and hyperpigmentation .
Other manifestations
Constitutional symptoms including fever, fatigue, and weight loss are frequently seen in MRH. Involvement of other organs such as the muscles, bones, thyroid glands, salivary glands, lymph nodes, lung, heart, liver, genital tract, kidney, eyes, and the gastrointestinal tract have been occasionally reported ( Table 1 ). Lung involvement includes pleural effusion, pulmonary infiltrates, hilar adenopathy, and interstitial fibrosis. Heart involvement has been reported as pericardial effusion and myocarditis. To our knowledge, no other cases of MRH with thrombosis have been reported, except one case of MRH complicated by central retinal vein thrombosis . Thus, our index case was the second reported case of MRH with associated thrombosis .
| 1. | Constitutional | Fever, fatigue, and weight loss |
| 2. | Musculoskeletal | Symmetrical polyarthritis, involvement of the distal interphalangeal joint, erosive arthritis, and arthritis mutilans |
| 3. | Cutaneous | Papulonodular lesions, photodistributed macular eruptions, and periungual telangiectasia |
| 4. | Lung | Pleural effusion, pulmonary infiltrates, interstitial fibrosis, and hilar adenopathy |
| 5. | Heart | Pericardial effusion and myocarditis |
| 6. | Gastrointestinal | Liver and spleen |
| 7. | Urogenital | Genital tract and kidney |
| 8. | Others | Muscle, thyroid glands, salivary glands, lymph nodes, and eyes |
Differential diagnosis from rheumatology perspective
Coexistence of MRH with autoimmune diseases is reported in approximately 15% of cases. Coexistent RA, systemic lupus erythematosus, SS, dermatomyositis, polymyositis, and scleroderma with MRH have been previously described . Differential diagnosis of MRH without cutaneous manifestations is mainly rheumatological, including nodular osteoarthritis (OA), RA, psoriatic arthritis (PsA), and gout ( Table 2 ).
| 1. | Coexistent disease | Rheumatoid arthritis, systemic lupus erythematosus, Sjögren’s syndrome, dermatomyositis, polymyositis, and systemic sclerosis |
| 2. | Arthritis | Nodular osteoarthritis, rheumatoid arthritis, psoriatic arthritis, reactive arthritis, and gout |
| 3. | Cutaneous | Dermatomyositis, sarcoidosis, lepromatous leprosy, granuloma annulare, and xanthoma |
| 4. | Others | Fibroblastic rheumatism, Farber’s disease, histiocytosis X, Langerhans, and non-Langerhans cell histiocytosis |
Differentiation between MRH and RA is based on the DIP joint and skin involvement, which favors the diagnosis of MRH. In MRH, RF and anti-CCP tests are usually negative. DIP joint involvement may also be seen in PsA and OA. The skin lesions of psoriasis are papulosquamous or pustular. Absence of periarticular osteoporosis, new bone formation, osteophytes, and ankylosis favors the diagnosis of MRH rather than PsA and OA. Marginal erosions, subchondral osteolysis, and widening of joint space also support the diagnosis of MRH .
Gout may involve the DIP joints and sometimes can be confused with MRH. However, unlike MRH, gout is usually associated with soft-tissue swelling and a nondemineralizing arthritis with central, marginal, or periarticular erosions with overhanging edges and reactive changes in the bone. Skin involvement is not a typical finding of gout and when present it is generally limited to the skin around the involved joints. The characteristic of gouty arthritis is the identification of typical urate crystals in the synovial fluid examination by polarized light microscopy .
The differential diagnosis of MRH includes rare rheumatologic conditions such as fibroblastic rheumatism, which may also affect the joints and the skin. However, the typical characteristics of fibroblastic rheumatism include Raynaud’s phenomenon, sclerodactyly, and juxta-articular osteoporosis, which are not reported in the subjects with MRH. In addition, fibroblastic rheumatism is not associated with malignancy or autoimmune disease .
When the predominant presentation of MRH is skin lesions rather than arthropathy, the differential diagnosis should include dermatomyositis, sarcoidosis, lepromatous leprosy, granuloma annulare, Farber’s disease, and xanthoma .
MRH associated with malignancy and other conditions
In about 25% of the patients, MRH may be associated with lymphoma, leukemia, myelodysplastic syndrome, and solid tumors such as lung, laryngeal, bronchial, ovarian, endometrial, cervix, stomach, colon, liver, mesothelioma, sarcoma, malignant melanoma, renal, bladder, penile, thyroid, and breast cancers ( Table 3 ). In case reports, MRH has also been associated with hyperlipidemia, IgG paraproteinemia, pregnancy, mycobacterial infections, primary biliary cirrhosis, organizing pneumonia, and thyroid disorders ( Table 4 ).
| Nasopharyngeal, bronchial, and lung |
| Ovarian, endometrial, and cervix |
| Scirrhous and invasive ductal carcinoma |
| Stomach, colon, and liver |
| Lymphoma, leukemia, and myelodysplastic syndrome |
| Melanoma |
| Renal, bladder, and penile |
| Sarcoma, unknown origin, mesothelioma, and thyroid cancer |
| Connective tissue disease | Others |
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