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Vasculitides mediated by immune complexes (ICs) Ahad Azmi. MD Rheumathologist

Vasculitis Definition: Inflammation within blood vessel walls (Presence of leukocytes in the vessel wall with reactive damage to mural structures )

Classification of Vasculitis in Adults Large Vessel Takayasu arteritis Giant Cell Arteritis Medium Vessel PAN Kawasaki’s Isolated CNS vasculitis Small Vessel Churg-Strauss Wegener’s Microscopic Polyangiitis HSP Essential Cryoglobulinemia Hypersensitivity vasculitis Vasculitis 2 nd to CTD Vasculitis 2 nd to viral infection

Further classification of small vessel vasculitides ANCA Positive Wegeners (90%) Microscopic Poly angiitis (70%) Churg-Strauss (50%) Drug-Induced (Hypersensitivity) ANCA Negative: HSP Cryoglobulinemia Hypersensitivity vasculitis

Vasculitides mediated by immune complexes (ICs): Are a clinically heterogeneous group of disorders linked by inefficient or dysregulated clearance of ICs

PATHOGENESIS ARTHUS REACTION formation of Ics ICs deposited within joints, blood vessels, and other tissues complement fixation, neutrophil recruitment, local inflammation, lysosomal release, oxygen free radical generation and tissue injury and causing disease ICs deposited in the blood vessel walls lead to vasculitis.

CUTANEOUS MANIFESTATIONS Small blood vessels Capillaries, postcapillary venules, and nonmuscular arterioles less than 50 μm in diameter Medium-sized blood vessels Between 50 and 150 μm in diameter Muscular walls

Palpable purpura:  The most common cutaneous finding in IC- mediated vasculitis  Extravasation of erythrocytes  Do not blanch  postinflammatory hyperpigmentation  symmetric fashion over dependent regions of the body, particularly the lower legs

Other skin manifestations: Vesicles Pustules Urticaria Superficial ulcerations Nonpalpable lesions (macules and patches) Splinter hemorrhages

PATHOLOGIC FEATURES Skin biopsy specimen  Light microscopy  Direct immunofluorescence (DIF).

HYPERSENSITIVITY VASCULITIS (CUTANEOUS LEUKOCYTOCLASTIC ANGIITIS) The term hypersensitivity vasculitis refers generally to an IC- mediated small vessel vasculitis of the skin that spares internal organs and usually follows drug exposures or infections

predominant cell type is the neutrophil The disease is characterized pathologically by IC deposition in capillaries, postcapillary venules, and arterioles

ACR 1990 Criteria for the Classification of Hypersensitivity Vasculitis ∗ Age >16 yr Use of a possible offending medication in temporal relation to symptoms Palpable purpura Maculopapular rash Biopsy of a skin lesion showing neutrophils around an arteriole or venule ∗ The presence of three or more criteria has a sensitivity of 71% and specificity of 84% for the diagnosis of hypersensitivity vasculitis.

TREATMENT Removal of the inciting agent is the most critical therapy for hypersensitivity vasculitis when the likely agent can be identified. In patients who have been exposed to multiple medications, determining the inciting agent may be difficult and may require the withdrawal of multiple agents simultaneously until the syndrome clears, typically in 1 to 2 weeks.

Treatment with glucocorticoids is reserved for patients with extensive disease and can usually be discontinued within several weeks Patients who experience repeated disease flares may need low-dose glucocorticoids to prevent recurrences Colchicine (0.6 mg twice daily) and dapsone (100 mg/day)

Prognosis: The prognosis for patients with hypersensitivity vasculitis depends on the inciting cause.

HENOCH-SCHÖNLEIN PURPURA (HSP)

DEFINITION: HSP is an IC-mediated form of small vessel vasculitis that is strongly associated with IgA deposition within blood vessel walls

Historical Description: 1808 Willan: noninfectious purpura had a predilection for lower extremities Schönlein: described association between purpura and arthritis Henoch: added description of gastrointestinal involvement and renal involvement Henoch: added description of renal involvement.

Majority of cases affect children younger than 5 years Adults can also be affected & have a greater tendency toward a prolonged disease course (with recurrent bouts of purpura) than do children.

True cause remains unknown Many cases occur after URTI (bacterial, viral)

The hallmarks of HSP: An URTI followed by a syndrome characterized by a purpuric rash, arthralgias, abdominal pain, and renal disease

Physical inspection of patient’s legs and buttocks

Colicky abdominal pain Sometimes the GI symptoms of HSP precede the onset of purpura, leading to a diagnostic quandary and occasionally to exploratory surgery Endoscopy may demonstrate purpura in the upper or lower intestinal tract

 Mild glomerulonephritis common and generally self-limited  End-stage renal disease rarely IgA Nephropathy. PAS stain of the glomerulus demonstrating mesangial proliferation and increase in matrix.

DIAGNOSIS: In children with mild manifestations, the clinical history alone may be sufficient to confirm the diagnosis In more serious cases (e.g., in the presence of renal involvement) or when there is sufficient doubt about the diagnosis, biopsy of an involved organ is essential

DIF reveals florid IgA deposition In the proper clinical setting, this finding is diagnostic of HSP Other forms of small vessel vasculitis may have small quantities of IgA within blood vessels

RENAL PRESENTATION IgA Nephropathy. Immunofluorescence of glomerulus demonstrating deposition of IgA in mesangial areas.

TREATMENT: In mild cases of HSP, no specific therapy is necessary Treat aggressive renal involvement with high- dose glucocorticoids & cyclophosphamide, azathioprine, or mycophenolate mofetil

 Recurrences of skin disease are not unusual  In a minority of patients, renal damage persists in the form of proteinuria and hematuria  Less than 5% of patients develop renal failure

C CRYOGLOBULINEMIC VASCULITIS

DEFINITION: Cryoglobulins are immunoglobulins characterized by a tendency to precipitate from serum under conditions of cold

Such proteins, detectable to a varying degree in a wide array of inflammatory conditions, do not always cause disease  Cryoglobulins bind to circulating antigen  Deposit in the walls of small & med-sized blood vessels  Activate complement Cryoglobulinemic vasculitis

Cryoglobulinemia has a tendency to involve medium & small-sized vessels Can be associated with the development of large cutaneous ulcers, digital ischemia, and livedo racemosa (findings of disturbances in medium-sized vessels)

Livedo reticularis

Three major types: Type I:  characterized by a monoclonal gammopathy (generally IgG or IgM)  Differs substantially from types II and III in its clinical presentation and disease associations  Type I cryoglobulinemia, associated with : Waldenström’s macroglobulinemia or, MM Hyperviscosity (dizziness, confusion, headache, and stroke)

Types II and III Are known as mixed cryoglobulinemias (composed of both IgG and IgM) In type II cryoglobulinemia : 90% hepatitis C + & the cryoproteins consist of monoclonal IgM and polyclonal IgG Non hepatitis C – Cases: Mixed essential cryoglobulinemia

Type III cryoglobulinemia :  Associated with polyclonal IgG and polyclonal IgM  Is associated with many forms of chronic inflammation, including infection and autoimmune disease.

Type II and III cryoglobulinemias : A triad of signs and symptoms: purpura, arthralgias, and myalgias Other organ systems commonly involve in mixed cryoglobulinemia are the kidneys and peripheral nerves & may cause a mem-Proliferative GN It may also cause a vasculitic neuropathy, usually with sensory symptoms predominating over motor symptoms.

Skin biopsy: Light microscopy of purpuric lesions : leukocytoclastic vasculitis DIF : various types of IGs & C deposition

Serologic testing To assay for serum cryoglobulins, the blood is collected in a prewarmed apparatus, allowed to clot at 37°C before processing, and then refrigerated at 4°C for several days. The percentage of the serum occupied by the cryoprecipitate is referred to as the “cryocrit.” The difficulties involved in performing cryoglobulin assays often lead to false-negative results Nonspecific serologic testing may also implicate mixed cryoglobulinemia

Cryoglobulins detected are not always associated with disease A strong clue is the presence of an extremely low level of C4, reduced out of proportion to C3 The monoclonal component of type II cryoglobulins almost invariably has RF activity (i.e., binds to the Fc portion of IgG) Thus, essentially all patients with type II cryoglobulinemia have high titers of rheumatoid factor As markers of clinical disease activity, C4 levels, rheumatoid factor titers, and cryocrits all fare poorly, often remaining abnormal in the face of clinically improved disease

Treatment:  Treatment of the underlying cause of the cryoglobulins is the only approach that leads to a long-term response  Immunosuppression alone is insufficient to treat cryoglobulinemic vasculitis that is driven by malignancy or chronic infection  In the case of hepatitis C: interferon-α and ribavirin)

Treatment: In severe consequences of cryoglobulinemia such as mononeuritis multiplex, glomerulonephritis, or extensive cutaneous ulceration: high-dose glucocorticoids and cyclophosphamide

If patients do not tolerate antiviral therapy well or if the treatment is ineffective, they may require low to moderate doses of prednisone to control the disease

The prognosis of patients with cryoglobulinemia generally depends on the underlying cause The outcome of type I cryoglobulinemia relates closely to the success in treating the cause. Type II or III cryoglobulinemia secondary to hepatitis C can be treated effectively if the viral infection is responsive to therapy.

URTICARIAL VASCULITIS

In contrast to common urticaria, the lesions of urticarial vasculitis (UV) last more than 48 hours, do not blanch when pressure is applied to the skin, and may leave postinflammatory hyperpigmentation Unlike common urticaria, the lesions of UV are frequently associated with moderate pain, burning, and tenderness in addition to pruritus

Whereas common urticaria typically resolves completely within 24 to 48 hours, the lesions of UV may take days to resolve completely, often leaving residual hyperpigmentation; they may worsen without therapy Three different syndromes of UV are recognized: normocomplementemic UV, hypocomplementemic UV, and the hypocomplementemic urticarial vasculitis syndrome (HUVS).

Normocomplementemic UV is typically a self-limited subset of hypersensitivity vasculitis In chronic cases, normocomplementemic UV must be distinguished carefully from neutrophilic urticaria, a persistent form of urticaria not associated with vasculitis In contrast, hypocomplementemic UV is more likely to be a chronic disorder that has certain overlapping features with SLE: low serum complements, autoantibodies, and an interface dermatitis characterized by immunoreactant deposition (complement and immunoglobulins) at the dermal- epidermal junction in a pattern essentially identical to the lupus band test

Finally, HUVS is a severe form of the disease associated with extracutaneous disease and an array of organ system findings atypical of SLE For example, HUVS may be associated with uveitis, COPD, and angioedema

The skin lesions in UV tend to be centripetal, favoring the trunk and proximal extremities more than dependent regions The lesions are painful and associated with a burning sensation rather than the pruritus of common urticaria. Biopsy of an urticarial wheal in UV demonstrates evidence of leukocytoclastic vasculitis, including injury to the endothelial cells of the postcapillary venules, erythrocyte extravasation, leukocytoclasis, fibrin deposition, and a perivascular neutrophilic (or, less commonly, lymphocytic) infiltrate

DIF demonstrates IC deposition around blood vessels in the superficial dermis and a striking deposition of immunoglobulins and complement along the dermal-epidermal junction In the proper setting, these findings (interface dermatitis as well as immunoreactant deposition within blood vessels) are diagnostic of hypocomplementemic UV HUVS, in contrast, is a clinical diagnosis based on the presence of UV and the occurrence of typical features in extracutaneous organ systems

Some cases of hypocomplementemic UV respond to therapies commonly used for the treatment of SLE, including low-dose prednisone, hydroxychloroquine, dapsone, or other immunomodulatory agents Serious cases of HUVS, particularly those presenting with glomerulonephritis or other forms of serious organ involvement, may require high doses of glucocorticoids and cytotoxic agents

Both COPD and cardiac valve abnormalities are associated with HUVS and may require specific treatment as well The prognosis of UV is linked to the disorder with which it is associated. SLE, COPD, angioedema, and valvular abnormalities are all known to occur in association with this disorder and may strongly influence both quality and quantity of life