Chapter 42. Miscellaneous Forms of Vasculitis

Essentials of Diagnosis

• Rheumatoid vasculitis usually occurs in patients with severe, long-standing, nodular, destructive rheumatoid arthritis, especially when the joint disease is “burnt out.”
• Palpable purpura, cutaneous ulcers (particularly in the malleolar region), digital infarctions, and peripheral sensory neuropathy are common manifestations.
• Tissue biopsy helps establish the diagnosis of rheumatoid vasculitis. Nerve conduction studies can identify involved nerves for biopsy. Muscle biopsies should be performed simultaneously with nerve biopsies to increase the diagnostic yield of the procedure.

General Considerations

Rheumatoid vasculitis (RV) is a medium-vessel vasculitis that occurs in patients with “burnt-out” but previously severe rheumatoid arthritis (RA). The typical patient has long-standing RA characterized by rheumatoid nodules, destructive joint disease, and high titers of rheumatoid factor. The diagnosis of RV should be considered in any patient with RA in whom new constitutional symptoms, skin ulcerations, serositis, digital ischemia, or symptoms of sensory or motor nerve dysfunction develop. RV resembles polyarteritis nodosa because it leads to multiorgan dysfunction in the skin, peripheral nerves, gastrointestinal tract, and other organs. Manifestations of RV, which resemble those of polyarteritis nodosa, include cutaneous ulcerations, digital ischemia, mononeuritis multiplex, and mesenteric vasculitis (see Chapter 35).

Pathogenesis

Immune complex deposition and antibody-mediated destruction of endothelial cells both appear to contribute to RV. Certain HLA-DR4 alleles that predispose patients to severe RA may also heighten patients’ susceptibility to RV. Cigarette smoking increases the risk of RV and has a synergistic interaction in this regard with antibodies to cyclic citrullinated peptides (anti-CCP antibodies). However, the inciting events leading to the development of RV among patients with previously destructive arthritis are not known. Factors in addition to vasculitis (eg, diabetes mellitus, atherosclerosis, and hypertension) likely play an important adjunctive role in promoting vascular occlusion, but the central issue in RV is necrotizing inflammation of blood vessels.

Clinical Findings

Symptoms and Signs

Skin

Dermatologic findings, the most common manifestation of RV, may include palpable purpura, cutaneous ulcers (particularly in the malleolar region), and digital infarctions (Figure 42–1).

Nervous System

A peripheral sensory neuropathy is a common manifestation of RV. A mixed motor-sensory neuropathy or mononeuritis multiplex may also be seen. Central nervous system manifestations (such as strokes, seizures, and cranial nerve palsies) are considerably less common.

Eyes

Retinal vasculitis as a manifestation of RV is common but frequently asymptomatic. Necrotizing scleritis and peripheral ulcerative keratitis (Figure 42–2) pose threats to vision and require aggressive immunosuppressive therapy.

Serositis

Pericarditis and pleuritis may occur in association with RV. Other cardiopulmonary manifestations of RV are unusual.

Laboratory Findings

Most laboratory abnormalities in RV such as elevations in the erythrocyte sedimentation rate are nonspecific and merely reflect the presence of an inflammatory state. Hypocomplementemia, antinuclear antibodies (ANAs), atypical antineutrophil cytoplasmic antibodies (ANCAs) (by immunofluorescence testing but not enzyme immunoassay; see Chapter 32), and anti-endothelial cell antibodies are all detected more frequently in patients with RV than in those with RA alone. All of these tests, however, are nonspecific.

Imaging Studies

The presence of bony erosions is a risk factor for the development of RV, but plain radiographs and other imaging studies have no consistent role in the evaluation of this disorder.

Special Tests

Because the treatment implications for RV are so severe, the diagnosis must be established by tissue biopsy whenever possible. Deep skin biopsies (full-thickness biopsies that include some subcutaneous fat) taken from the edge of ulcers are very useful in detecting the presence of medium-vessel vasculitis. Nerve conduction studies help identify involved nerves for biopsy. Muscle biopsies (eg, of the gastrocnemius muscle) should be performed simultaneously with nerve biopsies.

Differential Diagnosis

Patients with erosive RA are at increased risk for infections. When patients with RA seek medical attention for the new onset of nonspecific systemic complaints, the possibility of infection must be considered first. Cholesterol emboli may cause digital ischemia and a host of other signs and symptoms that mimic vasculitis. Diabetes mellitus is another major cause of mononeuritis multiplex, but multiple mononeuropathies occurring over a short period of time are unusual in that condition. Many clinical features of RV mimic those of polyarteritis nodosa and other forms of necrotizing vasculitis.

Treatment

Therapy must reflect the severity of organ involvement. Small, relatively painless infarctions around the nail bed develop in some patients with nodular RA (Figure 42–3). Such lesions, known as Bywaters lesions, do not herald the presence of a necrotizing vasculitis and require no adjustment in the patients’ therapy. With other disease manifestations, however, such as cutaneous ulcers, vasculitic neuropathy, and inflammatory eye disease, glucocorticoids may be required. Glucocorticoids remain a cornerstone of therapy for RV but severe disease is treated generally with two agents, both for greater efficacy in controlling the vasculitis and for sparing of the potential adverse effects of high-dose glucocorticoids. Cyclophosphamide, used to treat many cases of RV, should be used with appropriate caution, given that many patients with RV suffer from substantial disabilities and the effects of previous immunosuppression at baseline. Tumor necrosis factor (TNF) inhibition and B cell depletion may both be effective strategies in RV and are likely safer than cyclophosphamide in most patients. For this reason, it is appropriate to use TNF inhibitors or rituximab before cyclophosphamide in patients who require more treatment than high-dose glucocorticoids alone.

Prognosis

RV is a treatable condition but the development of this complication in patients who usually already have significant impairment is a poor prognostic indicator.

Essentials of Diagnosis

• The hallmark of Cogan syndrome is the presence of ocular inflammation and audiovestibular dysfunction. These findings may be accompanied by evidence of a systemic vasculitis.
• Interstitial keratitis is the most common form of ocular involvement.
• Audiovestibular dysfunction may lead to the acute onset of vertigo, tinnitus, nausea, and vomiting.
• Vasculitis in Cogan syndrome may take the form of aortitis, renal artery stenosis, or occlusion of the great vessels.

General Considerations

Cogan syndrome (CS), an immune-mediated condition that primarily affects young adults, is associated with ocular inflammation (usually interstitial keratitis) and audiovestibular dysfunction. This syndrome may be accompanied by a systemic vasculitis of large- and medium-sized arteries that may resemble Takayasu arteritis.

Pathogenesis

The onset of CS is frequently preceded by an upper respiratory tract infection. Because many features of CS can be caused by known pathogens (eg, Treponema pallidum), CS may be the direct consequence of an unidentified pathogen affecting the eyes, ears, and blood vessels. Alternatively, CS may be the indirect consequence of a pathogen that induces an immune response that continues to attack the host long after the pathogen has been eliminated (ie, molecular mimicry). Neither of these theories has been proved.

Clinical Findings

Symptoms and Signs

Eye

The most common ocular manifestation of CS is interstitial keratitis, which is characterized by the abrupt onset of photophobia, lacrimation, and eye pain. CS may also be associated with inflammation in other parts of the eye. Scleritis (Figure 42–4), peripheral ulcerative keratitis, episcleritis, anterior uveitis, conjunctivitis, and retinal vascular disease are all possible.

Ear

Patients with CS frequently suffer the acute onset of vertigo, tinnitus, nausea, and vomiting. These symptoms may be enormously disabling. The audiovestibular symptoms may occur before or after the onset of ocular disease, and are often separated in onset by weeks or months. If not treated promptly and aggressively, permanent hearing loss may ensue. Recurrent attacks, which are common, may cause decremental loss of hearing. Ultimately, complete hearing loss occurs in as many as 60% of patients.

Large-Vessel Vasculitis

The most common manifestation of vasculitis in patients with CS is aortitis. Aortitis may lead to dilatation of the aorta and subsequent incompetence of the aortic valve. Involvement of aortic branches (Figure 42–5) may cause arm or leg claudication. Renal artery stenosis or occlusion of the great vessels may also occur. These manifestations may be accompanied by nonspecific constitutional symptoms, such as malaise, fever, or weight loss as well as arthralgias and frank arthritis.

Laboratory Findings

Laboratory findings are nondiagnostic and generally reflect the presence of inflammation. An antibody against a 68-kD antigen has been identified in cases of autoimmune sensorineural hearing loss but is not found in patients with CS. Exclusion of syphilis with fluorescent treponemal antibody testing (ie, FTA-ABS, not just the rapid plasma reagin) is essential.

Imaging Studies

Gadolinium-enhanced T1-weighted magnetic resonance imaging (MRI) studies may demonstrate a hyperintensity in the membranous labyrinth secondary to vessel inflammation in the stria vascularis. This enhancement is not seen in patients with inactive CS and may be useful in identifying the activity of the disease. Brainstem MRI studies are also essential to exclude tumors of the cerebellopontine angle, which may mimic the audiovestibular features of CS. Angiography may be useful to define the involvement of the great vessels (Figure 42–5). Magnetic resonance angiography is useful in evaluating vessel wall thickness and edema as well as the degree of luminal stenosis.

Special Tests

Formal audiometric testing is important early in the evaluation to distinguish conductive hearing loss from sensorineural hearing dysfunction. In CS, audiometry demonstrates sensorineural hearing loss that preferentially affects the low- and high-range frequencies. This may be a useful way to document response to therapy, although subsequent hearing loss is not always due to active disease.

Differential Diagnosis

The differential diagnosis of immune-mediated inner ear disease (ie, sensorineural hearing loss with or without vestibular dysfunction) is shown in Table 42–1. Inflammatory eye disease may be caused by a variety of pathogens, including bacterial (eg, Chlamydiae, Neisseriae), spirochetal (eg, Borrelia burgdorferi), viral (eg, herpes simplex, varicella zoster), and mycobacterial (eg, Mycobacterium tuberculosis, M leprae).

Treatment

Some manifestations of CS respond well to symptomatic therapy. In general, the ocular manifestations are more amenable to therapy than the auditory complications. Interstitial keratitis may be treated with topical atropine or glucocorticoids. Sensorineural hearing loss in CS is analogous to rapidly progressive glomerulonephritis in other forms of systemic vasculitis: prompt treatment with immunosuppression is indicated. In addition to glucocorticoids, cyclophosphamide, azathioprine, methotrexate, and mycophenolate mofetil have all been used. The basis for choosing among these agents is largely empiric. The role for biologic agents, if any, has not been defined. For patients with advanced, irreversible hearing loss, hearing aids and cochlear implants may help. Vestibular retraining may be required for some patients with significant cochlear damage.

Complications

The prevention of complications depends directly on the rapid recognition of this diagnosis, and the equally swift institution of therapy. Permanent damage may result early in the course of immune-mediated inner ear disease, and hearing deficits will not respond to therapy if initiated too late. Therefore, a high index of suspicion for this diagnosis must be maintained when evaluating patients with compatible complaints.

Prognosis

Even if the initial event is recognized and responds to therapy, recurrent bouts of sensorineural hearing loss may cause the gradual loss of hearing. Up to 60% of patients experience some degree of permanent hearing loss. Some patients become completely deaf.

Essentials of Diagnosis

• The lesions of urticarial vasculitis are frequently associated with burning or pain rather than pruritus and require more than 24 hours to resolve.
• Immunofluorescence on skin biopsy specimen is the critical test. Intense staining for immunoreactants (ie, IgG, IgM, C3, C4, C1q) not only in and around small blood vessel walls but also in a ribbon along the dermal/ epidermal junction is pathognomonic of hypocomplementemic urticarial vasculitis.

General Considerations

Urticarial vasculitis (UV) is a leukocytoclastic vasculitis that presents as hives (often associated with pain or discomfort) that last longer than 24 hours. Although UV is occasionally seen in isolation, it most often appears in association with connective tissue disorders such as serum sickness, cryoglobulinemia, and systemic lupus erythematosus (SLE).

UV targets the capillaries and postcapillary venules in the skin, leading to the appearance of hive-like lesions. In evaluating patients with this problem, it is critical to distinguish cases associated with hypocomplementia from those in which the serum complement levels are normal.

Hypocomplementemic UV is associated with depressed serum levels of C3 and C4 and often with antibodies directed against the C1q component of complement. Such cases often overlap with known connective tissue disorders, particularly SLE. At the severe end of the spectrum of this disorder are patients with a distinct disorder known as the hypocomplementemic urticarial vasculitis syndrome (HUVS).

The normocomplementemic form is a subset of cutaneous leukocytoclastic angiitis (see Chapter 37) in which the leukocytoclastic vasculitis manifests clinically as urticaria. In general, these cases are secondary to “hypersensitivity” reactions (usually caused by a medication) and respond to discontinuation of the offending agent. This form of UV is not discussed further in this chapter.

Pathogenesis

Hypocomplementemic UV is mediated at least in part by immune complex deposition. In one model, following an unknown inciting event, the deposition of IgG and C3 leads to further complement activation. The complement cascade activates mast cells and eosinophils, both of which act to form the typical urticarial wheal. The eosinophils are gradually replaced by neutrophils, leading to the leukocytoclastic destruction of capillary walls. Antibodies to C1q are a marker of hypocomplementemic UV and likely contribute substantially to the finding of hypocomplementemia because they target an early component of the classical pathway of complement activation. The trigger(s) for anti-C1q antibodies remain unknown, and their full role in disease pathogenesis remains to be elucidated. Antibodies to C1q are not entirely specific for hypocomplementemic UV; they are also found in SLE.

Clinical Findings

Symptoms and Signs

The lesions of UV, typically between 0.5 and 2.0 cm in diameter (Figure 42–6), are frequently associated with burning or pain rather than pruritus. In contrast to common urticaria, UV lesions usually require more than 24 hours to resolve, and typically leave small amounts of hyperpigmentation in the skin, caused by red blood cell extravasation.

Like SLE, hypocomplementemic UV may also be associated with malaise, arthralgias, fever, and glomerulonephritis. Unlike SLE, HUVS is characterized not only by recurrent or chronic UV, but also by angioedema. Moreover, severe chronic obstructive pulmonary disease (COPD) and uveitis—manifestations that are atypical of SLE—often complicate this condition. Jaccoud arthropathy has been noted in some patients with HUVS and possibly correlates with the presence of cardiac valvular lesions.

Laboratory Findings

Serum C3, C4, and CH50 levels are depressed. Hypocomplementemic UV is generally accompanied by the presence of anti-C1q autoantibodies. The presence of these antibodies is not pathognomonic, since they also may be found in patients with SLE who do not have UV. Patients with hypocomplementemic UV have ANAs and, if significant overlap with SLE is present, may also have other autoantibodies (eg, anti-dsDNA, anti-Ro/SS-A, anti-La/SS-B, anti-Sm, and anti-RNP).

Special Tests

Hematoxylin and eosin staining of skin biopsy specimens reveal a leukocytoclastic vasculitis in the superficial dermis. Older lesions may have a predominantly lymphocytic infiltrate. The critical test is the performance of immunofluorescence on the skin biopsy specimen, which reveals intense staining for immunoreactants (ie, IgG, IgM, C3, C4, C1q) not only in and around small blood vessel walls but also in a ribbon along the dermal/epidermal junction. These findings are pathognomonic of hypocomplementemic UV.

Differential Diagnosis

The skin lesions of hypocomplementemic UV must be distinguished from common urticaria (which is characterized by pruritic lesions that resolve completely over 2–8 hours, leaving no traces of the original lesion), neutrophilic urticaria (a persistent, treatment-refractory form of urticaria not associated with vasculitis), and normocomplementic UV (see above).

Treatment

UV may respond to therapies commonly used in SLE, such as low-dose prednisone, hydroxychloroquine, dapsone, or other immunomodulatory agents. There is anecdotal evidence that antihistamines, calcium channel antagonists, doxepin, methotrexate, indomethacin, colchicine, and pentoxifylline are effective in some cases.

HUVS is frequently a therapeutic challenge. Serious cases, particularly those presenting with glomerulonephritis or other organ involvement, may require treatment with high doses of glucocorticoids, cyclophosphamide, or cyclosporine. Dramatic anecdotal success has also been reported with infliximab, an inhibitor of TNF. Angioedema, COPD, and cardiac valvular abnormalities may all necessitate other specific interventions.

Prognosis

Hypocomplementemic UV frequently reflects the presence of an underlying disorder, which may influence the prognosis substantially. HUVS may be associated with multiple complications (eg, severe COPD) that affect prognosis adversely.

Essentials of Diagnosis

• New lesions come in the form of tender papules, associated with pruritus or a burning sensation.
• Lesions develop into red, reddish-brown, or purple papules or nodules.
• Lesions may coalesce to form large plaques, usually over the extensor surfaces of joints.

General Considerations

Erythema elevatum diutinum (EED) is a chronic, recurring cutaneous vasculitis in which tender papules appear on the extensor surfaces of the extremities. The onset of these lesions is usually heralded by the presence of pruritus or stinging, followed by the development of tender papules or nodules that coalesce with others to form plaques. The skin findings are frequently located near joints, such as on the extensor surfaces of the hands and fingers.

Pathogenesis

The pathogenesis of EED is unknown but may involve recurrent immune complex deposition, followed by incomplete attempts at healing. Persistence of an antigen, with a subsequent increase in dendrocyte activity, may also play a role in its pathogenesis. There is an association between EED and multiple infections (including HIV, hepatitis B and C, tuberculosis, and streptococcal infections), autoimmune diseases (such as RA, relapsing polychondritis, and type 1 diabetes mellitus), and the paraproteinemias (such as multiple myeloma).

Clinical Findings

Symptoms and Signs

A new lesion is heralded by the presence of pruritus or a burning sensation in the skin, which then leads to the development of a red, reddish-brown, or purple papule or nodule. These lesions may coalesce to form large plaques, usually over the extensor surfaces of joints. With healing, the lesions often assume a yellowish or brown color, resembling xanthomata.

Laboratory Findings

Patients in whom EED is suspected should be screened for possible causes, including HIV infection, viral hepatitis, syphilis, cryoglobulinemia, and monoclonal gammopathy. When appropriate, patients may benefit from screening for associated autoimmune diseases as well.

Special Tests

Skin biopsy specimens usually show a nonspecific leukocytoclastic vasculitis with C3 deposition and are important for excluding non-vasculitis mimickers. In older lesions, the neutrophils are replaced by histiocytes, and there is marked granulation tissue and fibrosis.

Differential Diagnosis

Biopsy of lesions at various stages of development may demonstrate findings that are also consistent with a wide variety of diagnoses, including Sweet syndrome, pyoderma gangrenosum, drug reaction, erythema multiforme, fibrous histiocytoma, Kaposi sarcoma, xanthoma, and necrobiotic xanthogranuloma. The diagnosis can be established only by clinical judgment, supplemented by supportive findings on pathology.

Treatment

When a cause can be established, EED may respond to treatment of the underlying disorder. It is well established, for instance, that patients with EED as a consequence of HIV infection experience a regression of the cutaneous lesions with institution of highly active antiretroviral therapy. Nonspecific therapies are less successful. Lesions may be suppressed by dapsone but tend to recur when the drug is stopped. Lesions may also respond to tetracycline, colchicine, chloroquine, and glucocorticoids (either topical or systemic).

Complications

Although recurrent and frequently unresponsive to therapy, EED is limited to the skin and does not lead to significant morbidity.

Prognosis

The prognosis associated with EED itself, even when unresponsive to therapy, is generally quite good. The overall prognosis for the patient, however, largely depends on the underlying disease process.

Essentials of Diagnosis

• Cutaneous eruptions, such as palpable purpura or a maculopapular rash limited to the lower extremities, are the most common manifestation of drug-induced ANCA-associated vasculitis.
• Frequently associated with very high titers of anti-myeloperoxidase ANCA.
• Tissue biopsy provides a definitive diagnosis.

General Considerations

Drug-induced, ANCA-associated vasculitis (AAV) is a form of vasculitis induced by certain medications in some patients. The majority of cases are associated with ANCA directed against myeloperoxidase, often in very high titers. Drug-induced AAV may resolve following discontinuation of the offending agent. Other cases, however, are indistinguishable from idiopathic AAV and require intensive therapy with glucocorticoids and cytotoxic agents.

Many cases of drug-induced AAV are associated with relatively minor symptoms (eg, constitutional symptoms, arthralgias or arthritis, and purpura). Propylthiouracil is a well-documented cause of drug-induced AAV. Other drugs implicated thus far include hydralazine, sulfasalazine, minocycline, D-penicillamine, ciprofloxacin, phenytoin, clozapine, allopurinol, and pantoprazole. Leukotriene inhibitors have been linked to the occurrence of the eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome), but the true direct relationship (if any) between these medications and that condition remains unclear (see Chapter 34).

Pathogenesis

All of the events in the pathogenesis of drug-induced AAV remain undefined. Propylthiouracil is known to accumulate within neutrophil granules and alter myeloperoxidase, an event that may trigger the production of anti-myeloperoxidase ANCA. The presence of this human model of ANCA-associated disease forms one of the strongest arguments for a direct contribution of ANCA to the pathophysiology of other human disorders. Recent mouse models also strongly support the concept that ANCA may be pathogenic in humans.

Clinical Findings

Symptoms and Signs

Cutaneous eruptions are the most common manifestation of drug-induced AAV. These often present as palpable purpura or a maculopapular rash limited to the lower extremities. Unlike other AAV, the skin lesions in the drug-induced form frequently appear in “crops” (ie, simultaneously). Arthralgias and myalgias are common. The kidneys and upper respiratory tract may also be involved, as with the classic forms of AAV.

Laboratory Findings

In drug-induced AAV, very high titers of anti- myeloperoxidase antibodies are characteristic. Reports of cases associated with anti-proteinase 3 antibodies are rare. Even when the vasculitis resolves after discontinuation of the causative agent and initiation of immunosuppression, ANCA titers often remain elevated.

Special Tests

Tissue biopsy is usually necessary to provide a definitive diagnosis.

Differential Diagnosis

Drug-induced AAV is frequently slow to resolve after cessation of the offending agent and may be difficult to distinguish from the primary ANCA-associated vasculitides. In general, the manifestations of drug-induced AAV are mild and responsive to short courses of immunosuppression, although this is not always the case.

Treatment

The first step in treatment is the identification of the potential offending agents. Clinicians should take into account all exposures during the 6 months before the onset of symptoms, including nonprescription medications, herbal and dietary supplements, and illicit substances. Withdrawal of the offending agent may result in the resolution of the symptoms, although this may take months and may require the withdrawal of numerous agents simultaneously.

Patients with severe organ involvement may require aggressive immunosuppression with glucocorticoids and cytotoxic agents such as cyclophosphamide. The required length of therapy in drug-induced AAV may be shorter than that recommended for primary AAV.

Prognosis

Overall, the prognosis associated with drug-induced AAV is quite good. Organ involvement is frequently limited to the skin, and even systemic involvement frequently responds to lower doses of immunosuppressive agents administered for shorter periods of time than that required for primary AAV.