Vasculitis

Definition

Vasculitis is a disease in which autoimmune processes cause inflammation of arteries, arterioles, capillaries, veins and veins. This inflammation initially affects the wall of the blood vessels, but can also spread to the surrounding connective tissue. These two mechanisms can lead to damage to all organ systems of the body (skin, connective tissue, muscles, internal organs and brain).

Vasculitides occur as single diseases (= primary vasculitides) or in the context of other diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) or scleroderma but also in the context of infections (hepatitis) (= secondary vasculitides).

A commonly used classification of vasculitis is based on the size of the affected vascular system (Chapel Hill classification (1)):

Table 1. Chapel Hill classification of vasculitis

Frequency and incidence

Vasculitis is a rare disease with an approximate annual incidence of 19. 8 / 1 million. The peak of the disease is at the age of 65-74 where men are slightly more affected than women.

Pathogenesis

The pathogenetic mechanisms that lead to the development of vasculitis are different for the individual forms of vasculitis and are not fully clarified in detail. Type I immune reactions (IgE-mediated anaphylactic reactions) play a role in the development of Churg Strauss syndrome, type II reactions (mediated by cytotoxic autoantibodies) are associated with Wegener's disease, microscopic polyangiitis and Kawasaki syndrome. Effects mediated by the deposition of immune complexes (type III reactions) are found in polyarteritis nodosa, purpura Schönlein-Henoch and cryoglobulin vasculitis. Type IV reactions (a delayed response mediated by cells, especially T cells) are important for the development of giant cell arteritis and Takayasu arteritis.

Clinic and progression

As with any inflammation, vasculitis also causes a swelling, in this case of the vessel wall, which in extreme cases can shift or close the entire blood vessel. This results in a more or less abrupt interruption of the food and oxygen supply of the respective downstream organs, and the resulting clinical symptoms.

However, due to the different vascular systems involved in the individual vasculature, the complaints and symptoms can be so varied that there is no truly “typical” symptom. Clearly, the closure of a major blood vessel at the heart leads to very different complaints than a mere inflammation of the skin vessels. Many vasculitis suffer from non-specific symptoms such as fever, muscle and joint pain, night sweats and weight loss which do not necessarily immediately suggest the presence of vasculitis.

In the following, the clinical features of the most important vasculitis are briefly presented.

• Giant cell arteritis (Arteritis regionalis)
  Giant cell arteritis is a granulomatous vasculitis that mainly affects the large and medium-sized arteries of the head. As a first symptom, patients often report a new onset, usually one-sided temporal headache, which is often aggravated by chewing (Claudicatio masticatoria). Also typical is a one-sided, sudden onset of high-grade vision loss up to blindness, which occurs in about 30% of patients. Some of the patients have thickened, hard, increasingly winding and pressure-sensitive temporal arteries on the temples (hence the previously commonly used term of temporal arteritis). General symptoms such as fever, weight loss, tiredness, tiredness and muscle pain are also common.
  
  Giant cell arteritis is associated with polymyalgia rheumatica (PMR) in about half of the cases. PMR itself is an etiologically unclear picture of the disease in the elderly (> 60 years of age). Patients complain of pain and stiffness with movement restrictions of muscular origin in the neck area and bilateral of shoulder and/or pelvic girdle. Remarkable is usually a significantly increased blood lowering (> 40mm / h). Typically, treatment with corticosteroids leads to a sudden improvement of the symptoms.
   
• Takayasu Arteritis
  Takayasu Arteritis is also a granulomatous vascular disease and mainly affects young women under 40 years of age. Symptoms include general inflammatory reactions such as fever, night sweats, weight loss and pain in the limbs, as well as symptoms caused by the closure of large vessels such as the aorta and its outgoing branches. These include circulatory disorders in the extremities, dizziness, fainting attacks, visual disturbances, stroke and high blood pressure.

• Polyarteritis nodosa (PAN)
  PAN causes inflammation of the small and medium arteries with a pearl-like arrangement of the inflammatory nodes, mainly affecting the lower legs, forearms and internal organs.
  In about 80% of patients neuropathies can be found and also involvement of the central nervous system, which manifests itself in visual disturbances, strokes or seizures, may occur. Renal involvement usually manifests as renal infarction, or as secondary hypertension due to microaneurysms of the renal vessels. Glomerulonephritis, on the other hand, is atypical for PAN. Angina pectoris complaints and heart attacks may be an expression of cardiovascular involvement. Livedo reticularis, subcutaneous aneurysms – palpable as nodules (“nodosa”) – are among the skin manifestations. Pulmonary involvement is not usually found and rather indicates the presence of microscopic polyangiitis.
   
• Kawasaki syndrome
  Kawasaki syndrome mainly affects young children and initially resembles infectious diseases such as measles or scarlet fever. Asians are disproportionately affected by the disease. The main symptoms include fever (over about 10 days), mucosal symptoms (redness and swelling of the mucous membranes of the mouth and throat), a ‘coloured’, usually non-itchy, trunk-like rash without blisters, redness and painful swelling of the back of the feet and hands, and enlargement of the cervical lymph nodes.
   
• Morbus Wegener
  Wegener's disease is a necrotizing, granulomatous inflammation of the vessels in the upper (nose, sinuses, middle ear, oropharynx) and lower airways (lung). In about 80% of cases there is a renal involvement in the form of glomerulonephritis. Symptoms include throat/nose/ear complaints (rhinitis, sinusitis, septal perforations, ulcers), kidney complaints (glomerulonephritis), lung complaints (pluritis, haemoptysis, pulmonary circular clots and infiltrates) and eye complaints (conjunctivitis, scleritis, dacrozystitis). Furthermore, joint and muscle pain, skin symptoms (ulcers, gangrene) but also cardiac involvement (peri-, endo- and myocarditis) may occur.
   
• Churg Strauss syndrome
  In the case of Churg Strauss syndrome, the inflammatory tissue is mainly infiltrated by eosinophilic granulocytes. The actual vasculitic phase of the disease is often preceded by allergic rhinitis and/or allergic asthma by years to decades. During the actual vasculitic phase, eosinophilic infiltration into the lungs and digestive tract and associated symptoms such as asthma, sinusitis and rhinitis as well as gastrointestinal haemorrhage, appendicitis, pancreatitis or gastroenteritis with nausea and diarrhoea occur. In addition, joint inflammation, skin manifestations, involvement of the nerves (multiplex mononeuritis) or a cardiovascular manifestation may occur. Renal involvement usually manifests as arterial hypertension and uremia.
   
• Microscopic Polyangiitis

  Microscopic polyangiitis has long been regarded as a sub-form of polyarteriitis nodosa (hence also the abbreviation “mikroPAN”) but – also with regard to the pathogenetic mechanism – represents a unique picture of the disease. Often the vasculitic phase is preceded by a prodromal phase lasting months to years, which is partly characterized by ENT symptoms – similar to Wegener’s disease – and partly by uncharacteristic complaints on the part of the musculoskeletal system with myalgia and myositis, arthralgia and also arthritis. The life-threatening pulmonary full picture, which often requires intensive care, is based on pulmonary capillary disease with alveolar hemorrhagic syndrome and renal capillary disease, which is clinically manifested as rapidly progressive renal failure due to rapid progressive glomerulonephritis (RPGN). Both organ function limitations may also occur in isolation.

• Schönlein-Henoch purpura
  In most cases, Schönlein-Henoch purpura is a disease of children (< 10 years of age) that occurs after a previous respiratory infection or other triggers (e. g. medication). It begins acutely and often proceeds in the form of several flare-ups. Usually the disease heals without late consequences. The main symptom (but only in about 50% of cases also the first symptom) is the typical palpable purpura. These are reddish-brownish, somewhat raised and therefore palpable, skin lesions, which cannot be pushed away with a glass spatula, with petechiae of different sizes, some of which flow together, which occur symmetrically, and for hydrostatic reasons, on the extensor sides of the legs and buttocks. Clinically, in addition to fever and a severe feeling of illness, arthralgia, abdominal colic with bloody stools and nephritis with hematuria and proteinuria are impressive.
   
• Vasculitis in essential cryoglobulinaemia
  Cryoglobulins are cold-elabile antibodies that become insoluble in cold and in
  Heat dissolves again. Cryoglobulins cause increased viscosity, complement activation, coagulation activation and endothelial cell damage. This results in mostly acral cutaneous or systemic vasculitic lesions. Skin symptoms include palpable purpura and Raynaud symptoms, possibly with necrosis in the area of the acre. In addition, arthralgia and myalgia, renal involvement, polyneuropathy as well as cardiac and cerebral manifestations are common.
   
• Cutaneous leukocytoclastic vasculitis
  The cutaneous form of leukocytoclastic vasculitis is a disease limited to the skin. There are (often after drug abuse or after recent infections) especially in the trunk area reddish-brown, easily palpable small-diameter skin elevations.

Diagnosis

Due to the wide range of clinical symptoms that can occur in the context of vasculitis, and which can naturally also have many other causes, the diagnosis of vasculitis is often not made at the first attempt, but in some cases also represents an exclusion diagnosis, which can only be further confirmed by collecting individual indications. In particular, vasculitis must be included in the differential diagnosis in the case of unclear inflammatory multisystem diseases. If vasculitis is suspected, a further comprehensive investigation (including evaluation of all organ systems) is necessary. For this purpose, a careful and comprehensive history (as far as possible) is important, which should also include an accurate history of previous illnesses (allergic asthma/rhinitis).

Blood tests

General inflammatory parameters (increased blood-lowering, CRP, leukocytosis) may be the first indication of inflammation in the body, but are by no means indicative of the presence of vasculitis.

Some types of vasculitis are characterised by the presence of certain autoantibodies in the blood. Of particular importance are the so-called ANCA (anti-neutrophil cytoplasmic antibodies) which are directed against intracellular parts of white blood cells (neutrophil granulocytes) and which not only serve as diagnostic markers but also play a role in the development of the disease. Based on the fluorescence pattern of ethanol-fixed neutrophil granulocytes, a distinction is made between c (=cytoplasmic, directed against the enzyme Proteinase 3) -ANCA and p (=perinuclear, directed against the enzyme myeloperoxidase) -ANCA. c-ANCA can be detected especially in Wegener's disease, p-ANCA especially in microscopic polyangiitis and Churg-Strauss syndrome. However, as can be seen from the table, ANCA (including the associated vasculitides) are never positive in 100% of the cases and can also be detected with varying frequency in a number of other diseases.

Table 2. Frequency (%) of detection of c-ANCA and p-ANCA in different diseases.

Different organ parameters are used to assess a possible organ involvement. These include, for example, serum creatinine values in combination with qualitative and quantitative urinary analyses to assess renal function or the analysis of flushing fluid after bronchial lavage.

Different imaging methods (vascular ultrasound, computed tomography or magnetic resonance tomography of vessels, contrast agent angiography) are often used to draw conclusions on the presence of vasculitis. Ultimately, however, the proving and therefore also the gold standard for the diagnosis of vasculitis is the fine-tissue biopsy followed by microscopic examination (histology). This should be sought whenever possible for diagnosis. Due to the wide range of possible manifestations of the disease, joint care of the patient by doctors of different specialties (such as internists, ENT doctors, ophthalmologists, neurologists and dermatologists) is of great importance.

Therapy

The treatment of vasculitis is carried out individually depending on the type, extent and severity of the disease. Due to their rapid onset of action, excellent anti-inflammatory activity and wide dosage possibilities, glucocorticoids are a fixed component of the therapy. Initially higher doses are often used but can be gradually reduced if appropriate response is given.

In severe forms of vasculitis, especially if there is a particular risk for the patient due to the involvement of organs (lung, heart, CNS, kidney), medications such as cyclophosphamide (endoxane) must also be used. Such drugs are intended to suppress the autoimmune reaction directed against the body's own structures (so-called immunosuppressive therapy). Cyclophosphamide is usually given over a period of 6 months. Due to the pronounced effect and the possibility of adverse reactions, patients receiving immunosuppressive therapy should be closely monitored in order to initiate timely corrective measures if necessary.

Other immunosuppressive drugs such as azathioprine (Imurekâ) or methotrexate (Ebetrexate) may also be used in mild cases or following treatment with cyclophosphamide. Depending on the course of the disease, these drugs usually have to be taken over a longer period of time, sometimes over years. Therefore, even during therapy with these drugs, regular check-ups by the treating physician are absolutely necessary.

Among the other drugs and forms of therapy that have been used to treat vasculitis so far are preparations that are counted to the so-called biologics. However, TNF-alpha blockers, which are currently one of its main agents, have not shown any significant effect in patients with Wegener's disease (2) or patients with giant cell arteritis (3). On the other hand, rituximab (mabtheraâ), which causes selective destruction of B cells, has been shown to have a significant effect in patients with ANCA-positive Wegener's disease (4, 5).

Furthermore, especially in patients who develop plumorenal syndrome in the context of systemic ANCA-positive vasculitis, plasmapheresis therapy is often performed. This strategy is based on the consideration that plasmapheresis removes the pathogenic agent (ANCA).

Forecast

The prognosis depends on the type of vasculitis and its extent. Some forms of vasculitis (e. g. vasculitis in the context of hypersensitivity reactions) have a high rate of spontaneous healing and also patients with adequately treated giant cell arteritis do not have an increased risk of mortality compared to the corresponding age group (6, 7). The 5-year mortality rate, on the other hand, is up to about 40% for polyarteritis nodosa and up to 30% for Wegener's disease despite cyclophosphamide therapy, in particular the extent of organ involvement is decisive for the prognosis (6, 8).

Although vasculitis can be completely reduced by appropriate therapy, about half of the patients have to expect relapses or a recurrence of the disease (recurrence). This is possible even after years of complete freedom of appeal.

References

1. Jennette JC, Falk RJ, Andrassy K, Bacon PA, Churg J, Gross WL, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187-92.
2. Etanercept plus standard therapy for Wegener's granulomatosis. N Engl J Med. 2005;352(4):351-61.
3. Hoffman GS, Cid MC, Rendt-Zagar KE, Merkel PA, Weyand CM, Stone JH, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis: a randomized trial. Ann Intern Med. 2007;146(9):621-30.
4. Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U. Rituximab for refractory Wegener's granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med. 2006;173(2):180-7.
5. Flossmann O, Jones RB, Jayne DR, Luqmani RA. Should rituximab be used to treat antineutrophil cytoplasmic antibody associated vasculitis? Ann Rheum Dis. 2006;65(7):841-4.
6. Matteson EL, Gold KN, Bloch DA, Hunder GG. Long-term survival of patients with Wegener's granulomatosis from the American College of Rheumatology Wegener's Granulomatosis Classification Criteria Cohort. Am J Med. 1996;101(2):129-34.
7. Matteson EL, Gold KN, Bloch DA, Hunder GG. Long-term survival of patients with giant cell arteritis in the American College of Rheumatology giant cell arteritis classification criteria cohort. Am J Med. 1996;100(2):193-6.
8. Guillevin L, Le Thi Huong D, Godeau P, Jais P, Wechsler B. Clinical findings and prognosis of polyarteritis nodosa and Churg-Strauss angiitis: a study in 165 patients. Br J Rheumatol. 1988;27(4):258-64.