Pathology of relapsing polychondritis

INTRODUCTION — Relapsing polychondritis (RPC) is characterized by widespread, potentially destructive, inflammatory, and degenerative lesions.

While ear cartilage involvement has been classically associated with RPC, the disease may involve cartilage and biochemically and immunologically related connective tissue structures throughout the body (table 1). (See "Clinical manifestations of relapsing polychondritis".)

This topic will review the pathologic changes associated with RPC. The pathogenesis of this disorder is discussed separately. (See "Etiology and pathogenesis of relapsing polychondritis".)

HISTOLOGY OF A TYPICAL ACTIVE EAR LESION — Biopsy findings of an active ear lesion can be representative of pathologic changes occurring at connective tissue sites elsewhere. There is a characteristic spectrum of changes that depends upon the time the biopsy is performed.

●A pleomorphic perichondral infiltrate of lymphocytes with a variable proportion of polymorphonuclear cells, monocyte/macrophages, and plasma cells is initially observed at the chondro-dermal junction (picture 1). Lymphocytes dominate with CD4 helper T cells exceeding CD8 cytotoxic T cells [1]. Contiguous regions of cartilage show evidence of proteoglycan depletion. Coarse granular deposits consisting primarily of immunoglobulin G (IgG) and C3 can be localized by direct immunofluorescence at the junctional site.

●As the disease progresses, the integrity of cartilage is disrupted by invading granulation tissue, which tends to sequester islands of degenerating chondrocytes and depleted matrix (picture 2). IgG and C3 may be seen throughout the matrix. Matrix metalloproteinases (MMP) are expressed in both the perichondral granulation tissue and chondrocytes [2]. Chondrocyte apoptosis is increased in chondritis lesions and correlates with the expression of MMP-3 and cathepsin-K. Nitric oxide expression is increased, reflecting the chondrocyte production of pro-apoptotic MMPs.

●The late stage of the disease is characterized by complete disruption of tissue architecture and fibrosis (picture 3). Gelatinous cysts may be observed with focal regions of calcification and bone formation.

Electron microscopy shows prominent chondrocyte cytoplasmic processes extending into regions of damage [3]. These contain as-yet-to-be-identified small, electron-dense granules and vesicles of varying size, shape, and density.

The chondrocytes appear to be actively phagocytosing degraded material and are rich in lysosomes, lipid, and glycogen. Collagen and elastic fibers are eventually destroyed. Finely granular electron-dense material may be seen coating such fibers and may be on the surface of cartilage.

PATHOLOGY AT OTHER SITES — Other anatomic areas and organs that may be involved include the eyes, inner ear, nose, upper and lower airway, vascular system, skin, joints, kidney, and nervous system (table 1). (See "Clinical manifestations of relapsing polychondritis".)

Upper airway — Several structures localized in the upper airway can be affected due to relapsing polychondritis (RPC), including vocal cords, arytenoids, epiglottis, and subglottic space [4,5]. Direct visualization during acute episodes demonstrates erythema and edema. Chronic inflammation may result in scarring of tissue, leading to subglottic stenosis [6].

Lower airway — During acute inflammation, tracheal and bronchial mucosa may be erythematous and edematous [7]. Over time, due to recurrent episodes of inflammation, the cartilaginous structures can collapse, causing tracheomalacia and bronchomalacia as well as tracheobronchial thickening, fibrosis, and calcifications [8]. Patients with RPC can also have distal airway inflammation leading to air trapping.

Histologic findings of inflamed trachea due to RPC are variable and can depend on the disease stage. Acutely, the inflammation is lymphocyte predominant with plasma cells, neutrophils, and eosinophils [7,9]. Fibrosis is seen in chronic inflammation [9].

Aorta — At sites of aortic involvement, the media appears vascularized, and there is lymphocyte cuffing of the vasa vasorum. Mononuclear cell infiltration occurs with depletion of glycosaminoglycan content and with subsequent fragmentation and destruction of collagen and elastic fibers. Inflammation may extend throughout the aortic wall [10]. Smooth muscle destruction may lead to aneurysm formation. The aortic ring may be dilated, and valve leaflets may be thickened or ruptured.

Synovia — Synovial tissue biopsies have shown a chronic synovitis with edema and mononuclear cell infiltration.

Kidney — Renal pathology is rare and variable in RPC because of its association with diverse autoimmune and connective tissue diseases and with immunoglobulin A (IgA) nephropathy (table 2) [11,12]. As a result, renal involvement may reflect both RPC and the related diseases. Three major changes have been attributed to RPC [11]:

●Mild mesangial matrix expansion and cell proliferation

●Segmental crescentic necrotizing glomerulonephritis

●Tubulointerstitial disease

Mesangial deposition of IgG, IgM, and/or C3 may be seen by immunofluorescent microscopy, correlating with electron microscopic evidence of electron-dense mesangial deposits. Variable degrees of vascular and glomerular sclerosis and of tubular loss have been observed at necropsy.

Eye — In the eye, episcleral vessels may be surrounded by plasma cells, lymphocytes, and mast cells; there may also be a vasculitis with immunoglobulin deposition in scleral and conjunctival vessels [13]. These changes may be associated with loss of basophilia and fragmentation of elastic tissue at the scleroconjunctival angle. A case of RPC-manifesting chronic bilateral follicular conjunctivitis has been described, with conjunctival biopsy demonstrating a granulomatous obliterative microangiopathy with numerous eosinophils, plasma cells, lymphocytes, and epithelioid cells in the substantia propria [14]. The chronic conjunctivitis resolved following use of systemic methotrexate, indicating that such a presentation may be indicative of smoldering RPC and may be a harbinger of potential visceral disease.

Inflammatory cells may infiltrate the peripheral region of the cornea, which can show edema and necrotic changes. The iris may also be infiltrated with chronic inflammatory cells and may contain granulation tissue.

Optic neuropathy, an uncommon feature of RPC, has been attributed to ischemia, intrinsic inflammation of the optic nerve, or spread of inflammation to the nerve from adjacent intraconal orbital tissues. There is a description of optic neuropathy associated with periosteal thickening and enhancement in the apical orbit and in the adjacent intracranial space consistent with periostitis [15].

Central nervous system — In the brain, the inflammatory infiltrates are usually perivascular and consist of lymphocytes, plasma cells, and macrophages [16,17]. Patients with RPC can have limbic encephalitis, panencephalitis, and meningitis. Cerebrospinal fluid (CSF) examination findings include lymphocytic pleocytosis [18-22].

SUMMARY

●Relapsing polychondritis (RPC) is characterized by widespread, potentially destructive, inflammatory and degenerative lesions. Ear cartilage is classically affected, but RPC may involve cartilage and biochemically and immunologically related connective tissue structures throughout the body. (See 'Introduction' above.)

●There is a characteristic spectrum of pathologic changes that depends upon the duration of involvement at a given site. A pleomorphic perichondral infiltrate of lymphocytes with a variable proportion of polymorphonuclear cells, monocyte/macrophages, and plasma cells is initially observed at the chondro-dermal junction, along with coarse granular deposits consisting primarily of immunoglobulin (Ig) and complement. Contiguous regions of cartilage show evidence of proteoglycan depletion. (See 'Histology of a typical active ear lesion' above.)

●As the disease progresses, the integrity of cartilage is disrupted by invading granulation tissue, which tends to sequester islands of degenerating chondrocytes and depleted matrix. Chondrocyte apoptosis related to increased expression of matrix metalloproteinases (MMPs) and nitric oxide are part of the primary process of cartilage damage. The late stage of the disease is characterized by complete disruption of tissue architecture and fibrosis. Gelatinous cysts may be observed with focal regions of calcification and bone formation. Collagen and elastic fibers are eventually destroyed. (See 'Histology of a typical active ear lesion' above.)

●At sites of aortic involvement, the media appears vascularized, and there is lymphocyte cuffing of the vasa vasorum. Mononuclear cell infiltration occurs with depletion of glycosaminoglycan content and with subsequent fragmentation and destruction of collagen and elastic fibers. Inflammation may extend throughout the aortic wall. Smooth muscle destruction may lead to aneurysm formation. The aortic ring may be dilated, and valve leaflets may be thickened or ruptured. (See 'Aorta' above.)

●The upper and lower airway mucosa may be edematous and erythematous. Chronic inflammation can lead to subglottic stenosis and tracheobronchomalacia. (See 'Upper airway' above and 'Lower airway' above.)

●Synovial tissue biopsies have shown a chronic synovitis with edema and mononuclear cell infiltration. (See 'Synovia' above.)

●Renal pathology is variable in RPC because of its association with diverse autoimmune and connective tissue diseases and with IgA nephropathy. As a result, renal involvement may reflect both RPC and the related diseases. (See 'Kidney' above.)

●In the eye, episcleral vessels may be surrounded by plasma cells, lymphocytes, and mast cells; there may also be a vasculitis with immunoglobulin deposition in scleral and conjunctival vessels. These changes may be associated with loss of basophilia and with fragmentation of elastic tissue at the scleroconjunctival angle. Involvement of the conjunctiva, cornea, and iris may occur. Optic neuropathy is uncommon. (See 'Eye' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Clement J Michet, MD, who contributed to an earlier version of this topic review.