Multicentric reticulohistiocytosis (MRH) is a rare systemic granulomatous disorder of unknown cause seen in adulthood and is characterized by the proliferation of the histiocytes (macrophages) in the skin, the mucosa, the subcutaneous tissue, and the synovium. It was first described in 1937 as a nondiabetic cutaneous xanthomatosis. The disorder has been also called lipoid dermatoarthritis, reticulohistiocytoma, lipid rheumatism, giant cell reticulohistiocytosis, giant cell histiocytoma, and giant cell histiocytosis. Goltz and Lymon proposed the name multicentric reticulohistiocytosis for this condition in 1954 because of the multifocal origin and systemic nature of the disease. It usually begins during the fourth decade of life, and women are more commonly affected than men, with ratio 3:1. In ˜60% to 70% of patients, polyarthralgia is the first manifestation of the disease. Approximately 25% of cases have been associated with the presence of neoplasia, including all types of cancer, solid and hematologic. MRH frequently coexists with autoimmune diseases, including Sjögren syndrome, systemic lupus erythematosus, scleroderma, and dermatomyositis. Occasionally, nonautoimmune conditions have been associated with MRH, such as diabetes mellitus, thyroid disease, colitis, and dyslipidemia.

Laboratory markers are poorly sensitive and not specific for MRH. About half of the patients show elevated erythrocyte sedimentation rate and C-reactive protein. Serum autoantibodies are only occasionally detected and generally support the coexistence of an autoimmune disorder. Histopathologic findings include histiolymphocytic infiltrate within the dermis with small, sometimes multinucleated histiocytes. These cells are not foamy, which allows distinguishing them from other forms of histiocytic disorders, such as sarcoidosis or xanthogranulomatosis. More advanced dermal lesions are characterized by the pathognomonic multinucleated giant cells with a ground-glass eosinophilic cytoplasm (megalocytes). Additional findings include a strong positivity of histiocytes for periodic acid-Schiff (PAS) and expression of acid phosphatase, nonspecific esterase, and lysozyme. Triglycerides, cholesterol, and phosphate esters appear to be present in the lesion, suggesting either that histiocytes are stimulated to produce these substances or that this is a form of lipid storage disease. Immunohistologically, MRH histiocytes express positivity for tartrate-resistant acid phosphatase (TRAP), CD68, CD45, MAC387, vimentin, lysosome, and human alveolar
macrophage 56 (HAM-56); however, there is conspicuous negativity for S100 protein, CD1a, and factor XIIIa. Furthermore, the synovial fluid mononuclear cells from patients with MRH express macrophage-specific markers including CD11b, CD14, CD68, and class II HLA DR. Quantitative amounts of proinflammatory cytokines are elevated, including TNF-alpha, IL-6, IL-12, and IL-1-beta. More recent data support the hypothesis that synovial fluid macrophages may differentiate into osteoclasts following RANKL pathway activation or macrophage colony-stimulating factor (M-CSF) as suggested in other inflammatory diseases. Ultrastructurally, the histiocytes resemble type A synoviocytes. The cytoplasm contains osmiophilic membrane-bound lysosomal granules, often closely associated with a single large stellate Golgi apparatus.

Clinical findings include characteristic cutaneous manifestations appearing as translucent brown-reddish to fleshcolored papulonodular lesions of variable sizes (1 mm to 1 cm or larger) (Fig. 10.4). The other clinical features may be very similar to those of rheumatoid arthritis, consisting of soft tissue swelling, stiffness, and tenderness of the joints. Unlike rheumatoid arthritis, however, the distal interphalangeal joints are most frequently affected. Less commonly affected are the proximal interphalangeal, metacarpophalangeal, shoulder, and elbow joints. Occasionally, the articular lesions may be marked by severe destruction similar to arthritis mutilans of rheumatoid arthritis or psoriatic arthritis (Figs. 10.5 and 10.6). The characteristic absence of significant periarticular osteoporosis distinguishes this disorder from the inflammatory arthritides, and there is also no periosteal new bone formation, which distinguishes it from psoriatic arthritis or juvenile idiopathic arthritis. Lack of osteophytes and interphalangeal ankylosis, and the presence of soft tissue nodules and atlantoaxial abnormalities including subluxation and erosion of the odontoid process distinguish this arthropathy from erosive osteoarthritis. At times, the pattern of bone erosions with sclerotic margins and overhanging edges, and the presence of soft tissue masses, may mimic those of gout (Fig. 10.7). Unlike gout, however, there is symmetrical distribution of the lesions in the hands and feet and lack of calcification within soft tissue nodules.

Treatment consists of systemic steroids, cytotoxic drugs such as cyclophosphamide, chlorambucil, methotrexate, leflunomide, and infliximab. Bisphosphonates such as alendronate and zoledronate have been reported to improve skin lesions and arthritis.

Sarcoidosis is a systemic inflammatory disorder predominantly affecting young adults, characterized by the presence of noncaseating granulomas in affected organs. The disease has a worldwide distribution, with the greatest incidence in Sweden. Although the etiology still remains unsettled, the evidence that sarcoidosis most commonly involves the lungs, eyes, and skin, focused the search for environmental causes such as exposures to airborne antigens. In fact, some of the earliest studies have reported association of sarcoidosis with exposures irritants found in rural settings, such as emissions from wood-burning stoves and tree pollen. More recently, association of sarcoidosis with exposure to inorganic particles, insecticides, and moldy environments has been suggested. Currently, the investigators found compelling evidence to support the hypothesis implying certain environmental foreign nonparticulates as a plausible cause of this condition in individuals with a genetically based immune dysregulational predisposition. Some researchers suggested that a predisposition to acute sarcoid arthritis is carried by the HLA DQ2-DR3 haplotype that appears to be transmitted as a dominant genetic trait. Many genetic associations have been linked sarcoidosis with genes within the major histocompatibility complex (MHC) locus. Most recent studies suggested the novel gene BTNL2 (butyrophilin-like) has been associated with sarcoidosis of Caucasian patients. The active granulomatous inflammation is associated with a dominant expression of T-helper (Th) 1 cytokines (interferon gamma [IFN-gamma]), interleukin-12 and IL-18, and tumor necrosis factor (TNF).