Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are uncommon disorders with similar joint and skin manifestations. They are usually included among the non-Langerhans histiocytoses, but recent insights drive some criticism. The diagnosis is often challenging and must be confirmed by the histological typical features. If the skin manifestations are missing, the arthritic complaints may be confused with those of other rheumatic disorders. In these cases, only a careful clinical and radiological evaluation leads to the correct diagnosis. The natural course of the diseases may rapidly develop into disabling manifestations, making an aggressive treatment strongly recommendable. There is emerging evidence that anti-tumour necrosis factor-α agents and bisphosphonates are promising drugs for MRH, while a course of methotrexate and steroids seems to be the best option for FR. Finally, the clinician should be aware that in many cases MRH, but not FR, is associated with a large number of systemic manifestations and with malignancy. This eventuality must be accurately ruled out.
Multicentric reticulohistiocytosis (MRH) and fibroblastic rheumatism (FR) are two uncommon dermato-arthropathies sharing some clinical and radiologic features. Both the diseases are characterised by a destructive polyarthritis with similar erosive aspects and by cutaneous involvement with papules and nodules. However, the histopathological features are clearly different, a multinucleated giant cell with ‘ground glass’ appearance of the cytoplasm being the hallmark of MRH and myofibroblasts in a network of thickened collagen being that of FR.
Classification
MRH and FR are usually classified among the non-Langerhans histiocytoses. Histiocytoses comprise a heterogeneous, confounding group of disorders in which various tissues, including skin and other organs, are infiltrated by overgrowing cells of the mononuclear phagocytic system arising from the common CD34 + precursor cell. These disorders are currently identified by histopathology and by immunohistochemical differentiation of their component cells.
According to the Histiocyte Society recommendation, the histiocytoses have been categorised in Langerhans cell histiocytoses (class I), non-Langerhans cell histiocytoses (non-LCH) (class II) and malignant histiocytoses (class III) . Based on the ontogeny of the cells, class II was further subdivided into class IIa, in which there is a predominance of dermal dendritic cells, and class IIb involving cells other than Langherans cells and dermal dendrocytes. In this last subgroup were included MRH and FR.
In the right clinical contest, lesional cells that are CD1a+/Langerin +/S100+ can be identified as Langerhans cell. The non-LCH are defined by the accumulation of histiocytes that do not meet the phenotypic criteria for the Langerhans cells. These cells can develop either into the interstitial/dermal dendrocyte (S100-/CD68+/CD14+/Factor XIIIa+) or into the monocyte/macrophage lineage (S100±/CD68+/CD1a−), depending on the cytokine environment. Even after a cell has differentiated, often an intimate relationship remains with many functional, morphological or phenotypical overlaps showing that the demarcation between the groups is not always well defined .
From the clinical point of view, it has been proposed to divide the non-LCH into three groups: those that affect predominantly the skin (including juvenile xanthogranuloma and other disorders of the juvenile xanthogranuloma family), those that affect skin but have a major systemic component (among them MRH) and those that primarily involve extra-cutaneous sites (such as Erdheim–Chester and Rosai–Dorfman disease) .
Recently, another hypothesis arising from the evidence of the osteoclastic-like activity of the MRH cells has been proposed. These cells exhibit properties of osteoclast markers staining positively with tartrate-resistant acid phosphatase (TRAP) and cathepsin K. Moreover, by a receptor activator of nuclear factor kappa-B ligand (RANKL)-dependent mechanism, MRH synovial fluid macrophages may differentiate into mature functional osteoclasts that can carry out bone resorption and erosive arthritis. The therapeutic efficacy of bisphosphonates further implicate that the osteoclasts have a pathogenetic role. Although not completely specific, these data suggest that MRH may be considered a ‘systemic osteoclastic disease’ .
In the attempt to formulate a unifying concept for the non-LCH, Zelger et al. described five major morphological type of histiocytes, namely scalloped, vacuolated, xanthomatised, oncocytic and spindle cell, the last being the more mature type very resistant to treatment. Following this concept, FR has been included among the spectrum of the non-LCH, the presence of spindle-cell macrophages suggesting that they are another phenotypic expression of pluripotential histiocytes. Other arguments supporting this opinion were the clinical similarities with MRH as well as with other diseases comprised in this group.
However, histiocytic origin of the cells involved in FR is nowadays in doubt. In fact, recent immunohistochemical data have shown that most of the spindle-shaped cells of the FR nodules are calponin and smooth muscle actin (SMA) strongly positive, but clearly negative for most histiocytic/dendrocytic markers. Moreover, the spindle-shaped cells have the ultrastructural features typical of myofibroblasts, not of macrophages, failing to confirm an histiocytic origin of the disease. Therefore, FR should be considered a distinct clinic-pathologic entity that, given the clinical course and the biological data, could be properly added to the group of fibromatoses instead of histiocytoses . With further immunophenotypic studies, greater clarity should be achieved on this topic.
Multicentric reticulohistiocytosis
MRH is an uncommon disease characterised by prominent skin and joint manifestations. Systemic complaints are frequently present. An association with an underlying malignancy and an autoimmune disease is reported in about 30% and 15% of the cases, respectively. Therapeutic options continue to be a challenge and remain largely empirical. Histologically, the lesions show a characteristic infiltrate of histiocytes and multinucleated giant cells with eosinophilic ‘ground-glass’ cytoplasm. The cells are usually positive for CD45 and CD68, but they lack S100 and CD1a expression which characterise Langerhans cells, and therefore are thought to be of monocyte/macrophage lineage.
Apart from earlier vague reports, the first adequately described case of MRH was provided in 1937 by Weber and Freudenthal , while the term ‘multicentric reticulohistiocytosis’ was introduced in 1954 by Golz and Laymon . This designation has gained general acceptance over the years during which the disease has emerged as a definite clinical and pathological entity, replacing many other nowadays obsolete synonyms.
So far, about 250 cases have been reported, mostly as isolated cases or small series. For several reasons, it is very likely that this is an under representation of the disease. In the past, some reviews have appeared summarising the majority of published cases in the world literature .
Due to its rarity, data on the incidence and prevalence of MRH are unavailable. The disease has a worldwide distribution, the highest concentration in Europe and USA reflecting simply an increased awareness of this disorder in these countries.
MRH has not been shown to have a familial component. A very rare variant – familial histiocytic dermatoarthritis – characterised by familial occurrence of MRH associated with glaucoma, uveitis and cataracts was seldom described . MRH usually starts in patients in their fourth decade of life; however, cases in paediatric and in elderly people have been reported . Females are affected two–three times more often than males . Cases have been observed also in pregnant women .
Multicentric reticulohistiocytosis
MRH is an uncommon disease characterised by prominent skin and joint manifestations. Systemic complaints are frequently present. An association with an underlying malignancy and an autoimmune disease is reported in about 30% and 15% of the cases, respectively. Therapeutic options continue to be a challenge and remain largely empirical. Histologically, the lesions show a characteristic infiltrate of histiocytes and multinucleated giant cells with eosinophilic ‘ground-glass’ cytoplasm. The cells are usually positive for CD45 and CD68, but they lack S100 and CD1a expression which characterise Langerhans cells, and therefore are thought to be of monocyte/macrophage lineage.
Apart from earlier vague reports, the first adequately described case of MRH was provided in 1937 by Weber and Freudenthal , while the term ‘multicentric reticulohistiocytosis’ was introduced in 1954 by Golz and Laymon . This designation has gained general acceptance over the years during which the disease has emerged as a definite clinical and pathological entity, replacing many other nowadays obsolete synonyms.
So far, about 250 cases have been reported, mostly as isolated cases or small series. For several reasons, it is very likely that this is an under representation of the disease. In the past, some reviews have appeared summarising the majority of published cases in the world literature .
Due to its rarity, data on the incidence and prevalence of MRH are unavailable. The disease has a worldwide distribution, the highest concentration in Europe and USA reflecting simply an increased awareness of this disorder in these countries.
MRH has not been shown to have a familial component. A very rare variant – familial histiocytic dermatoarthritis – characterised by familial occurrence of MRH associated with glaucoma, uveitis and cataracts was seldom described . MRH usually starts in patients in their fourth decade of life; however, cases in paediatric and in elderly people have been reported . Females are affected two–three times more often than males . Cases have been observed also in pregnant women .
Clinical aspects
The onset of the disease is usually insidious: in the majority of patients the joint symptoms occur first, followed by skin manifestations. The latency from the articular onset of the disease and the cutaneous manifestations ranges from a few months to 6 or more years, with a mean of 3 years, making correct diagnosis difficult. Less frequently skin involvement occurs before or simultaneously with joint manifestations . Some patients with prominent dermatologic manifestations and minimal articular complaints have been described .
Arthritis
From the beginning, the arthritis tends to be symmetrical, maximally affecting interphalangeal joints of the hands. As with other more common inflammatory joint diseases, stiffness, swelling and moderate pain are the other prominent clinical features. Without the accompanying skin lesions, the arthritis is commonly misdiagnosed until the more evocative radiographic features and skin lesions appear.
Distal interphalangeal (DIP) joints are frequently involved (75% of patients), representing one of the clinically distinguishing features as well as a disparity between severity of joint destruction and subjective symptoms. In the absence of the typical skin manifestations, this clinical picture may be confused with Heberden’s nodes or with the articular manifestations of other rheumatic diseases . Knees, shoulders, wrists, hips, ankles, elbows and feet are the other most commonly affected areas, but any other joint may be involved, including occasionally temporo-mandibular and atlanto-axial .
In the past, the progression of the MRH arthropathy has been described as ‘rapidly destructive’ evolving into a severe and incapacitating disease; the younger the patient, the more likely the propensity for joint destruction. An end-stage ‘arthritis mutilans’ has been detected in about half of the patients . In recent years, when more aggressive therapies have been introduced, the progression tends to be described as ‘very slow’ with a lower incidence of disabling arthropathy than in the past (12% vs. 45%) . Either spontaneously or in response to therapy, the disease tends to wax and wane, gradually losing its activity, although the period of inflammatory activity may last 2–10 years or more. Obviously, the destructive sequelae lead to a chronic disability.
Cutaneous manifestations
Skin involvement consists of multiple flesh-toned to reddish-brown papules and nodules, most commonly located on the face, neck and hands ( Fig. 1 ). Sometimes itchy, they vary in size from a few mm to 2 cm, ranging in number from a few to a hundred. The facial distribution tends to include the ears, bridge of the nose and scalp. Vermicular lesions bordering the nostrils are considered pathognomonic . On the hands, they are particularly distributed to the dorsum and sides of the fingers. Around the nail folds, small papules represent a typical sign (so-called ‘coral beads’). The lesions have a tendency to a cefalo-caudal distribution with a decreasing number on the lower trunk and legs. They may occasionally coalesce to form large plaques giving a cobblestone appearance. In the worst cases, severe involvement of the face leads to a visually impressive disfigurement referred to as ‘leonine facies’ . Xantelasma-like patches involving the eyelids are evident in about 20% of patients. Nail changes including longitudinal ridging and hyperpigmentation result from involvement of the DIP joints or the nail bed matrix . A diffuse, irritable erythema or severe pruritus presenting as a photosensitivity dermatitis may precede the appearance of the nodules .
With increasing frequency has been reported, cases of MRH presenting with skin features closely mimicking those of dermatomyositis . Confusing features may be the erythematous rash in a fashion of photodistribution, papular lesions on the dorsum of the hands simulating Gottron’s sign and the periungueal telangectasia. In a review of the published cases of MRH, these features have been revealed as the presenting symptoms more commonly than previously thought (about 10% of the patients). Therefore having dermatomyositis-like features did not have an increased association with malignancy. Histological examination of skin biopsies allows the definite diagnosis.
Due to the distribution over the sun-exposed areas, it has been suggested that the skin eruptions of MRH are closely associated with a sunlight-induced Kőbner’s phenomenon . This hypothesis has been confirmed in a patient in whom repeated irradiation of ultraviolet B on the uninvolved skin resulted in the induction of the typical lesions .
Mucosal surfaces of the lips, tongue, gingiva or nasal septum are involved in over half of the cases. Vulvar and perianal lesions are described in isolated reports . Both the cutaneous and mucosal lesions repeatedly appear and regress spontaneously or with therapy.
Other systemic manifestations
Even if articular and cutaneous manifestations are prominent, it is now clear that MRH is a systemic disorder in which many tissues may be affected. In fact, the typical histology has been observed in biopsy and autopsy tissues from many organs. Sometimes the systemic involvement of the disease may be widespread.
Pulmonary symptoms were reported in 20% of the cases. Several authors have observed non-specific pathologic findings including pleural effusions, hilar adenopathy, pulmonary infiltrates and fibrosis in a background of usual interstitial pneumonia, but only in few cases the relationship with MRH was based on results of tissue examination . Constrictive pericarditis is the more frequent complication for the heart , and progressive heart failure due to myocardium involvement has been also described. Other manifestations include salivary gland enlargement, dysphagia, splenomegaly and involvement of submucosal tissue underlying a gastric ulcer . Muscle weakness with minimal non-specific chronic inflammation on biopsy has been suggested to be a typical finding of muscle disorder in MRH. In a few cases, symptoms of muscle disease were myositis like and dominated the clinical picture .
Fever, weight loss, general weakness and fatigue may be other constitutional accompanying features.
Associated diseases
MRH has been described in association with various conditions. Hyperlipidaemia and a positive tuberculin skin test have been identified in 30–58% and 12–50% of cases, respectively . As first noted by Barrow and Holubar in their review , a concomitant autoimmune disease has been reported in a significant percentage of cases (5–20% of the cases) ( Table 1 ). Although concurrence could be pure coincidence, a common autoimmune aetiology has been suggested .
| Sjőgren’s syndrome |
| Hypothyroidism |
| Primary biliary cirrhosis |
| Systemic sclerosis |
| Systemic vasculitis |
| Myositis |
| Celiac disease |
| Systemic lupus erythematosus |
| Rheumatoid arthritis |
| Diabetes mellitus |
MRH and malignancy
In different series and in the available review, a significant association of MRH with malignancy is reported in 15–31% of the retrieved cases. The association was observed with several carcinoma, breast and ovarian being the most often identified, but including also stomach, cervix, lung, colon, pancreas as well as mesotelioma, malignant melanoma, sarcoma, malignant lymphoma and leukaemia or even metastasis from an unknown primary tumour . MRH may occur also around the time of recurrence of metastasis of a previously diagnosed and treated cancer .
That high association rate has led some authors to indicate MRH as a paraneoplastic syndrome, but this deserves some criticism because no specific malignancy has been consistently reported in association with MRH, together with the fact that in all cases but one, , the evolution of the two diseases do not run a parallel course.
Notably, it is of the utmost clinical importance that the onset of MRH may be concurrent as well as precede the onset of the neoplasm . Even if MRH does not fulfil the criteria for a paraneoplastic disease, any patient with a diagnostic of MRH should undergo a thorough investigation to exclude malignancy.
Histopathology
The diagnosis of MRH is performed on the basis of the characteristic histopathologic findings of nodules in skin and/or synovial tissue. The typical infiltrate is composed of many mononuclear histiocytes and multinucleated giant cells 50–100 mm in diameter. Their cytoplasm is eosinophilic, periodic acid-Schiff (PAS) positive, finely granulated or with a ‘ground-glass’ appearance ( Fig. 2 ). The nuclei may be arranged haphazardly or may align along the periphery or cluster in the centre. Other inflammatory cells are also present, but in lesser numbers. In the earlier lesions, fewer giant cells and more oeosinophils, lymphocytes and histiocytes have been reported. In the later stages, an increasing number of giant cells have been emphasised. Finally, lymphocytes and giant cells decrease in number, fibroblasts appear and there is fibrosis. Some authors reported features of collagen phagocytosis in the cytoplasm of the cells .
Various histochemical studies have been performed in attempts to elucidate the nature of the material deposited in the cells. With different methods, the results suggest a non-specific accumulation of lipids (mainly neutral fat substances and phospholipids) and other PAS-positive diastase-resistant material, indicating the presence of a polysaccharide component other than glycogen or acid mucopolysaccharide. Electron microscopy studies confirmed the presence of dense granules with the morphology of lysosomes in the cytoplasm. Synovial lesions parallel those seen in the skin, but giant cells have been reported to be less numerous .
Immunohistochemical findings are variable and conflicting but, in more definitive reports, the data support the notion of monocyte/macrophage origin of both mononuclear and multinucleated giant cells. In fact, CD68 and CD45 expression are the most constant and reliable markers identified in these cells, being reported positive in all studies in which it was tested . Together with the negativity of S100, CD1a and Factor XIIIa, these data are consistent with a non-Langherans histiocytic disorder. Moreover, has been found that the proliferating cells stained for cytokines produced by activated macrophages – in particular tumour necrosis factor-α (TNF-α), interleukin (IL)-1β and IL-6 – that are also elevated in the serum, decrease after treatment . These data support the concept that MRH is a macrophage-reactive process where pro-inflammatory cytokines may be released locally and in the blood, which may account for the systemic symptoms.
Finally, it has been reported that the multinucleated giant cells exhibit an osteoclastic differentiation staining strongly with osteocleast tissue markers (TRAP and cathepsin) and are positive for CD10, a cell surface metallo-protease, which activity could account for the joint destruction .
Laboratory investigations
There are no specific or diagnostic laboratory tests for MRH. About half of the patients have a moderate increase in erythrocyte sedimentation rate (ESR) and a mild anaemia. Hyperlipidaemia is inconstant, and 5–30% of the cases have slight to moderate hypercholesterolaemia. A positive rheumatoid factor, anti-cyclic citrullinated antibodies, hypergammaglobulinemia and positivity for anti-nuclear antibodies have been noted only rarely, excluding the cases with an associated autoimmune disease .
Synovial fluid analysis has been performed on a few patients with highly variable results: synovitis may be present, with a wide range of cellularity from mild to highly inflammatory, with different types of cell populations. Mononuclear cells and lymphocytes are usually prominent in cases of moderate activity and polymorphonuclear granulocytes in the more inflammatory synovial effusions .
Radiology
Imaging plays a crucial role in the diagnosis of MRH and a careful radiological reading together with an accurate clinical examination is the key to the right identification of the disease .
The arthritis associated with MRH is typically erosive ( Fig. 3 ). The erosions, which reflect the evolution of the infiltrative granulomatous process, are initially well circumscribed and progress rapidly, spreading from the margins to the entire joint surface. These changes result in a widening of joint space, loss of cartilage and resorption of subchondral bone. Remarkably, osteoporosis and periosteal new bone formation are absent in the majority of cases, in contrast with other forms of inflammatory arthritis . The most characteristic sites of involvement are the interphalangeal joints (IP) particularly distal (DIP) of the hands, which can be affected in as many as 75% of the cases. The arthritis may progress very aggressively, leading to the disabling ‘opera glass’ deformity. An associated involvement of the wrists can be apparent. In the feet, the abnormalities resemble those of the hands, and all the appendicular skeletal joints may present similar changes. In the spine, bilateral, symmetrical erosions may affect the sacroiliac and costovertebral joints and bony ankylosing may develop without subchondral bony sclerosis. An atlanto-axial involvement with severe destructive abnormalities has been reported .
Differential diagnosis
In the absence of cutaneous manifestations, the diagnosis can be challenging and the patients with MRH are often misdiagnosed. The differential diagnosis of MRH must include all other causes of erosive polyarthritis, in particular FR, psoriatic arthritis, erosive osteoarthritis, elderly gout and rheumatoid arthritis ( Table 2 ) . A detailed analysis on this topic has been reported in our previous reports .
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