The patient was a 62-year-old woman with long-standing rheumatoid arthritis (RA), who was admitted to a tertiary center because of increasing disability and fatigue. She had been diagnosed with RA 10 years ago. A rheumatoid factor (RF) test at diagnosis had been positive, but there was no information on anticitrullinated peptide antibodies (ACPA). Her family history was unremarkable, and she was previously healthy apart from her RA. Previous antirheumatic treatment included sulfasalazine, which had been stopped because of gastrointestinal side effects, and hydroxychloroquine, which had been stopped because of lack of efficacy. The patient had been reluctant to start methotrexate because of fear of side effects. She was on long-term treatment with low-dose glucocorticoids (prednisolone 5 mg daily). She had mild disability, with limited hand function, but was able to work part time as a seamstress.
During the last year, she had experienced increasing tingling and numbness in the hands and feet, followed by severe pain that was not relieved by rest. Increasing doses of analgesics had only a moderate effect on this. There were also recurrent ulcers on the lower legs and the feet, which occurred without major trauma. She reported gradual, unintentional weight loss over 1 year of approximately 20 kg (from 68 kg to 48 kg). Finally, she had developed trouble walking due to a foot drop on the left side.
On admission, the patient looked thin but was in no immediate distress. There was no peripheral lymphadenopathy. Examination of the heart, lungs and the abdomen were unremarkable. There was synovitis of several proximal interphalangeal and metacarpophalangeal joints of both hands, and moderate ulnar deviation of the fingers. There were several small, well-defined, ulcers in various stages of healing on the tibial aspect of both legs, as well as on the heels and on the toes of the left foot. Neurologic examination revealed decreased sensibility to touch and pain in both lower extremities, and a foot drop on the left side.
Routine laboratory tests revealed a mild normochromic anemia, thromobocytosis and a slightly elevated C-reactive protein level. Liver function tests and white blood cell counts were normal.
Patients with severe, long-standing RA have an increased risk of comorbidities. The differential diagnoses in a patient who develops constitutional symptoms, such as weight loss, should include malignancies and chronic infections. Patients with poorly controlled RA are at an increased risk of non-Hodgkin lymphoma and severe infections. Overall, such complications in patients with RA are more likely to be due to the burden of inflammation than to side effects of immunosuppressive drugs. Early diagnosis, based on a careful evaluation of signs and symptoms, leading to appropriate treatment, is of major prognostic importance. In the present case, malignancy should be excluded, but the signs of neuropathy and the lower extremity ulcers are strongly suggestive of vasculitis. Lower leg ulcers in patients with RA may be associated with trivial trauma, and influenced by other factors including arterial insufficiency, repeated trauma, dependent edema, chronic glucocorticosteroid use, and smoking. Chronic or recurrent infection may also lead to impaired healing and should be excluded. In typical cases of systemic rheumatoid vasculitis, the ulcers are associated with an extensive rash and mononeuritis multiplex ( Fig. 4-1 ). Mononeuritis usually involves the peroneal or radial nerves. Initially, the mononeuritis is asymmetric but may become symmetrical. However, most cases of peripheral neuropathy in patients with RA are not due to vasculitis but rather to conditions such as local nerve compression and diabetes. Electroneurography should be performed, and a sural nerve biopsy may sometimes be helpful. Again, a pattern of nerve involvement with mononeuritis accompanied by polyneuropathy with neuropathic pain, additional extra-articular organ involvement, and signs of uncontrolled inflammation may all suggest vasculitis. A history of long-standing RA that was not aggressively treated with disease-modifying antirheumatic drugs (DMARDs) should also alert the physician to the possibility of extra-articular organ involvement. Low serum complement levels, indicating systemic complement consumption, is helpful in the diagnosis and indicates a poor prognosis in patients with systemic rheumatoid vasculitis.
RA-associated vasculitis occurs more frequently among smokers and among patients with rheumatoid nodules. Sometimes, the development of small ulcerations overlying a rheumatoid nodule may herald the presentation of more extensive vasculitic lesions ( Fig. 4-2 ).
Systemic rheumatoid vasculitis can affect other internal organs, although clinically evident vasculitic lesions in the coronary vessels or the central nervous system are rare. In the kidney, renal artery involvement, as occurs in polyarteritis nodosa with vasculitis, may cause renal failure, although the pathology is distinct from polyarteritis nodosa. More frequently, a pauci-immune glomerulonephritis occurs in RA, usually of the mesangioproliferative type. Furthermore, although systemic vasculitis associated with RA may affect the gastrointestinal tract, it is not usually associated with the development of microaneurysms.
Patients may be antinuclear antibody or perinuclear antineutrophilic cytoplasmic antibody (P-ANCA) positive in about one third of cases. A positive cytoplasmic antineutrophilic cytoplasmic antibody test (C-ANCA) is rarely seen, and especially if the ANCA is directed against proteinase-3 in a patient with RA, a second disease, such as primary systemic necrotizing vasculitis, should be suspected. However, the coexistence of RA and a primary systemic vasculitis in the same patient is rare.
The patient was a previously healthy 57-year-old male warehouseman. He had been smoking at least 10 cigarettes per day since his late teens. His uncle had recently died from pulmonary carcinoma, but there was no history of lung disease among his first-degree relatives. The patient presented to a primary care physician with reports of increasing shortness of breath on moderate exertion and migratory joint pain. An initial physical examination was unremarkable, and a chest radiograph showed only suspected thickening of the right pleura and nonspecific interstitial abnormalities. The patient was referred to a pulmonary disease specialist. When evaluated, the patient reported rapid worsening with severe dyspnea, left-sided thoracic pain, and stiffness of the hands. A new chest radiograph revealed a pleural effusion and progression of basal reticular pulmonary changes. The erythrocyte sedimentation rate and the C-reactive protein were moderately elevated, but there was no increased white blood cell count. Analysis of pleural fluid from a diagnostic thoracocentesis indicated an exudate with a low glucose level and a mixed pattern of inflammatory cells. On physical examination performed by a rheumatologist, symmetric polyarthritis of the hands and feet was noted. Serum tests for RF and ACPA were both positive at high antibody concentrations.
RA associated lung involvement may precede the clinical onset of arthritis, or the presentation of manifestations such as pleuritis and interstitial pneumonitis may occur simultaneously with rapidly progressing joint symptoms. Differential diagnoses include pulmonary infections and malignancies. In the present case, with a long history of smoking, a pulmonary carcinoma must be excluded. In particular, pleural effusions that are asymptomatic and only noted on clinical examination or radiographs may be due to malignancy. Cytologic evaluation of aspirated pleural fluid is of major importance. The presence of multinucleated giant cells is highly specific for rheumatoid pleuritis, but such cells are seen in less than 50% of these cases. A low glucose level and a high level of the soluble form of the interleukin-2 receptor in the pleural fluid compared with serum levels may also be helpful in distinguishing RA-associated pleuritis from other causes of chronic pleural exudates. In patients with lung manifestations due to RA and other connective diseases, an infectious origin is often initially suspected, but an atypical course with a poor response to antibiotics may suggest an underlying inflammatory disorder. High-resolution computed tomography and open lung biopsy are considered the gold standard for diagnosing interstitial lung disease. Histologic features from tissue obtained at lung biopsy include an inflammatory infiltrate with lymphocytes, plasma cells, and histiocytes with varying degrees of fibrosis, and may be classified as usual interstitial pneumonitis (IP) or nonspecific IP. Specific stainings have suggested a particular role for CD4+ T cells in patients with RA-associated IP, but not in patients with idiopathic IP ( Figs. 4-3 and 4-4 ). RA-specific dysregulation of T cells may be important in the pathogenesis of rheumatoid lung disease, with potential implications for targeted therapies. Furthermore, quantification of the CD20+ B-cell ( Fig. 4-5 ) infiltrates reveals them to be significantly greater in patients with RA-associated IP compared with those with idiopathic IP.
In patients with established RA treated with methotrexate, RA-associated IP must be distinguished from methotrexate-induced toxicity, which usually has a subacute onset with rapidly progressive respiratory symptoms, less radiographic evidence of fibrosis, and a histologic pattern dominated by eosinophilia and type II pneumocyte hyperplasia. In practice, the distinction between rheumatoid lung disease and methotrexate-related toxic pneumonitis may be possible only after extensive follow-up investigations, and many cases of chronic RA related IP are incorrectly suspected to be methotrexate induced at first presentation. Possible toxic drug reactions have also been reported in patients treated with leflunomide and tumor necrosis factor (TNF) inhibitors. The possibility of a superimposed respiratory tract infection must be considered in the setting of rapid progression of pulmonary symptoms in patients with suspected RA-associated or treatment related lung disease.
TREATMENT OF RHEUMATOID ARTHRITIS–ASSOCIATED VASCULITIS
Management of rheumatoid vasculitis remains largely empirical ( Table 4-1 ). Two open-label studies, as well as long-term clinical experience, favor the use of cyclophosphamide and high-dose glucocorticoids in patients with severe systemic rheumatoid vasculitis. Scott and Bacon compared intermittent bolus intravenous cyclophosphamide plus methylprednisolone, followed by maintenance therapy with azathioprine or oral cyclophosphamide, with other treatments in a non-randomized, open trial of 45 patients. The control group received continuous treatment with other drugs, mainly azathioprine, continuous oral corticosteroids (20–60 mg/day), D-penicillamine or chlorambucil. The age and sex distributions were similar in the two treatment arms, but the patients treated with pulsed cyclophosphamide tended to have more extensive organ involvement. Response to treatment in the first four months was more frequent in the cyclophosphamide group ( Fig. 4-6 ), which also had a lower rate of relapses over the following 4 years (24% versus 54%). Early improvements in the healing of leg ulcers as well as clinically significant improvements in sensory neuropathy occurred at higher rates in the cyclophosphamide group (see Fig. 4-5 ). Long-term clinical experience corroborates these findings. In particular, early and substantial reduction in neuropathic pain is often seen in RA patients, with vasculitis-related neuropathy treated with high doses of cyclophosphamide and methylprednisolone. In the study reported by Scott and Bacon, there was a striking improvement in mononeuritis, with complete resolution in all three patients treated with intravenous cyclophosphamide. However, in patients with long-standing motor deficits, only partial resolution may be possible due to irreversible neural damage. Serial measurements have indicated that clinical improvement following treatment with cytotoxic agents is associated with a decrease in immunoglobulin G RF levels and an increase in complement, which confirms the importance of immune complexes in this subset.
|Manifestation/Disease Subset||Treatment||Evidence Base||References|
|Systemic rheumatoid vasculitis||Cyclophosphamide (pulsed or oral) with high dose glucocorticosteroids||Nonrandomized, open label trials||( )|
|Systemic rheumatoid vasculitis refractory to cyclophosphamide||TNF-inhibitors||Case series||( )|
|Interstitial lung disease||Cyclosporin A||Case reports||( )|
|Rapidly progressing interstitial lung disease||Cyclophosphamide (pulsed or oral) with high-dose glucocorticosteroids||Extrapolation from trials of patients with scleroderma associated alveolitis||( )|
|Felty’s syndrome||Methotrexate||Case reports||( )|
|Intramuscular gold||( )|
|Systemic AA amyloidosis||Chlorambucil||Randomized controlled trial||( )|
|Systemic AA amyloidosis||Cyclophosphamide||Retrospective cohort study||( )|