Dimitrios A. Pappas and Joan M. Bathon Department of Medicine, Division of Rheumatology, Columbia University Medical Center College of Physicians and Surgeons, New York, NY, USA
RA complications; RA extra-articular features; RA extra-articular signs; Extra-articular involvement of RA; Nonarticular manifestations of RA, Systemic manifestations of RA
The term "extra-articular manifestations of rheumatoid arthritis" refers to involvement with disease oftissues and organs outside the joints. Itis believed that the same or similar cytokine pathway that drives synovitis may be the culprit for the involvement of extra-articular structures. Extra-articular involvement usually occurs in active, severe, and long-standing articular involvement.
Rheumatoid arthritis RA is an inflammatory disease manifesting primarily with joint
Inflammation which if not treated early and aggressively leads to articular destruction and decreased functionality.
Less commonly RA is complicated by involvement of organ systems other than the skeletal. Most organ systems may be affected to the degree that RA could be viewed not as a "purely" joint disease but as a multisystem entity. Some of these extra-articular manifestations have a significant impact on overall prognosis, are associated with more active articular disease, and correlate with worse morbidity and higher mortality.
Traditional reference textbooks would provide an extensive list of extra-articular RA manifestations spanning from most common to the rare ones. In this entry, an exhaustive description of each individual extra-articular manifestation reported in the literature will not be attempted. Instead, the most frequently encountered and the ones associated with grave prognosis and worse overall outcomes will be described. While overall the occurrence of extra-articular manifestations has not declined in the recent years Turesson et al. 2004, there is evidence that more aggressive therapy of rheumatoid arthritis may have contributed to a lower incidence of the most serious ones Bartels et al. 2010.
Rheumatoid nodules are the most common cutaneous manifestation in patients with rheumatoid arthritis Turesson and Jacobsson 2004. They manifest as subcutaneous firm growths on the extensor surface of extremities or joints olecra-non, extensor surface of forearm, achille tendon and at pressure points sacrum or occiput. Contrary to tophaceous growths, they are attached to the underlying periosteum. Rheumatoid nodules are almost exclusively encountered in patients with seropositive disease and associate with active erosive disease, smoking, and a higher likelihood of development of other extra-articular manifestations Nyhall-Wahlin et al. 2011. Occasionally, they can appear in internal organs such as the lungs but also in other tissues heart, meninges, and larynx.
Pathologically, they represent granulomata with fibrinoid necrosis in the center - frequently with evidence of small vessel vasculitis - surrounded by palisading macrophages and lymphocytes Palmer et al. 1987.
Treatment with methotrexate - and less frequently other DMARDs - can occasionally be associated with new nodules or an increase in number and/or size of nodules - a condition called methotrexate-induced accelerated nodulosis - but a causality link has not been established with certainty Patatanian and Thompson 2002. It can occur even after response of polyarthritis to therapy and also in seronegative patients
Kerstens et al. 1992.
Anemia of chronic disease - also referred to as "anemia of chronic inflammation"- is frequently encountered in patients with active articular disease along with frequent reactive thrombocytosis. Both abnormalities can improve with treatment of joint disease with anti-inflammatory and disease-modifying antirheumatic drugs DMARDs.
Leucocytosis may accompany steroid treatment or be indicative of underlying infection in this frequently immunocompromised population. Cytopenias may represent bone marrow suppression due to DMARD treatment.
Felty`s syndrome consists of neutropenia usually with detectable splenomegaly and occasionally accompanied by lower extremity skin ulcerations or concurrent thrombocytopenia. It is only rarely encountered - less than 1% - and is usually seen in long-standing seropositive nodular erosive disease Goldberg and Pinals 1980 and much less frequently at RA presentation or with inactive or "burned out" disease Balint and Balint 2004. It is associated with a higher risk for the development of other extra-articular manifestations Goldberg and Pinals1980. The major concern when Felty`s syndrome occurs is infections due to neutropenia.
Multiple possible mechanisms may participate in the pathogenesis of neutropenia in Felty`s syndrome ranging from impaired granulopoiesis due to antibody-mediated inhibition of granulo-cyte colony-stimulating factor, a maturation arrest in the bone marrow to increased destruction of neutrophils in the periphery due to immune complex-mediated reduced survival of neutrophils, or destruction via anti-granulocyte antibodies and sequestration in the spleen Rosenstein and Kramer 1991. Bone marrow examination usually demonstrates normal myeloid cellularity with maturation arrest in most of the cases Rosenstein and Kramer 1991. HLA DR4 antigen is present in higher frequency in patients with Felty`s syndrome than it is for the general RA population Dinant et al. 1980.
Treatment for Felty`s syndrome consists of treatment with DMARDs in the same manner active joint disease would be treated, which in most of the cases is simultaneously present with Felty`s. Methotrexate is the most frequently used agent while other agents have been used such as leflunomide, sulfasalazine, plaquenil, or gold Rashba et al. 1996. Steroids have and can be used but the concern of increasing the risk of an infection or further immunosuppressing already infected patients may complicate the therapeutic approach. In cases of significantly low neutro-phils and fear of or recurrent infections, granulo-cyte colony-stimulating factor G-CSF can be attempted Krishnaswamy et al. 1996 although reports mention an increased risk for a flare in articular disease. Resistant cases can be treated with splenectomy. Newer biologic therapies have been tried in case reports and series but have not been proven to be consistently effective Narvaez
Et al. 2012.
Large granular lymphocyte syndrome LGL is an entity with several similarities to Felty`s syndrome - sometimes called pseudo-Felty`s syndrome - but also with distinct differences. In LGL, an expansion of a clonal cytotoxic T-lymphocyte - or less commonly natural killer cells Loughran et al. 1993 - expressing a distinct set of surface markers is present and is accompanied by neutropenia and splenomegaly. There is peripheral lymphocytosis in contrast to Felty`s syndrome, and frequently, the total WBC count is normal. The bone marrow is infiltrated
With lymphocytes, and anemia and thrombocytopenia are common. LGL is not associated with erosive arthritis or other extra-articular manifestations, and it frequently presents concurrently with RA. Due to neutropenia, recurrent infections are common. Patients may die from lymphopro-liferative disease/leukemia Lamy et al. 2003. While splenectomy is a therapeutic modality for Felty`s syndrome, it can exacerbate LGL. Treatment for LGL syndrome is otherwise similar to this for Felty`s syndrome Rosenstein and Kramer 1991.
Patients with RA are at increased risk for lymphoproliferative malignancies and in particular non-Hodgkin`s lymphoma - most commonly large-cell B-cell lymphoma - compared to the general population Wolfe et al. 2004. The question as to whether the disease itself or treatment with nonbiologic or biologic DMARDs is responsible for this increased risk is still being debated
Wolfe et al. 2004.
The most frequent manifestation of RA in the eye is xerophthalmia resulting in keratoconjunctivitis sicca. Patients complain of dry eyes, a sensation of foreign body in the eye, burning, and possibly photophobia. The severity of isolated dry eyes does not seem to correlate with RA disease activity. However, secondary Sjogren`s syndrome sicca accompanied by xerostomia is most frequently encountered in patients with active uncontrolled RA Fujita et al. 2005.
Diagnosis of sicca is assisted by slit lamp examination and a Schirmer`s test. In cases where keratoconjunctivitis sicca is not associated with active RA, symptomatic treatment with artificial tears or oral cholinergic/muscarinic agents is beneficial. Topical cyclosporine is also used although it may take several weeks before the effect becomes apparent Barber et al. 2005. In resistant cases, punctal occlusion is offered as a therapeutic option. In the cases of secondary Sjogren`s associated with active RA, treatment directed to controlling synovial inflammation may offer control of xerophthalmia symptoms. Episcleritis presents in less than 1 % of the RA patients and manifests with a red eye accompanied by a dull orbital ache but usually with preserved vision. In contrast with scleritis - described below - episcleritis is a benign and usually self-limited entity which may be treated with topical or oral anti-inflammatory agents or steroids.
Scleritis is seen less commonly but is a serious ocular manifestation associated with grave prognosis as it may threaten the vision. It is usually associated with uncontrolled articular inflammation and sometimes with the coexistence of other extra-articular manifestations including vas-culitis Watson and Hayreh 1976. It frequently presents bilaterally which is in contrast with scleritis in the general non-RA population Fujita et al. 2005. Patients have severe pain, a red eye, and photophobia. If left untreated, scleritis may lead to severe damage of the sclera and scleromalacia. Treatment for scleritis consists of topical anti-inflammatory and steroid agents in combination with systemic steroid-sparing agents. For mild cases, oral NSAIDs can be used but frequently an increase in the dose of methotrexate or initiation of more potent agents such as cyclo-phosphamide with high dose steroids may be needed. Multiple other agents have been employed in the treatment of scleritis including the newer biologic agents such as TNF-a inhibitors Theodossiadis et al. 2007.
Less frequent eye manifestations comprise a wide spectrum of diseases including uveitis, ulcerative keratitis, scleromalacia perforans a condition of necrotizing scleritis without inflammation which leads to thinning of the sclera without symptoms or redness, and also complications relating to treatment with hydroxychloroquine which can cause both retinopathy and keratopathy or steroids which may increase the intraocular pressure leading to glaucoma or cataracts.
Rheumatoid vasculitis RV is the most serious extra-articular manifestation of RA. In fact
A vasculitic process is assumed to possibly underlie several other extra-articular manifestations such as the rheumatoid nodules and scleritis/episcleritis.
While early autopsy investigations reported the prevalence of RV to more than 15% and the lifetime risk to 2% Suzuki et al. 1994, more recent evidence shows a decline in incidence especially after the year 2000 Bartels et al. 2009, suggesting an association with the availability of newer agents to treat RA and the overall trend to treat articular disease more aggressively.
RV is associated with RA of long duration, severe destructive disease, seropositivity for rheumatoid factor and/or anti-CCP, and also nodules, certain HLA alleles, and smoking Voskuyl et al. 1996.
Small and medium vessels may be affected and biopsy shows leucocytoclasis or pauci-immune lesions. Essentially, every tissue may be affected, but most commonly the skin and peripheral nerves are targeted in RV. Mesenteric, cardiac, and renal involvement is rare. Patients may present with systemic symptoms of fatigue, fever, and weight loss, but concurrent active articular disease may confound the association of these symptoms with underlying or evolving vasculitis. Skin involvement may be in the form of palpable purpura or more commonly manifest as nail-fold infarcts and leg ulcerations. Occasionally digital ischemia leading to gangrene may be seen. A sensory or mixed sensory motor neuropathy indicates peripheral nerve involvement. Mononeuritis multiplex is a common presentation and patients may develop a foot or wrist drop in an acute fashion.
A solid diagnosis will require a skin or nerve biopsy to exclude atheromatous disease accounting for ischemia or extremity ulcerations, or other conditions such neutrophilic dermatoses that may also be encountered in patients with RA and account for ulcerations.
Treatment is usually tailored to the severity of RV. Traditionally nail-fold infarcts have been considered a benign manifestation which may respond to accelerated DMARD treatment for the underlying articular disease. Small skin ulcerations that do not expand may also be treated with low dose prednisone or DMARDs. However, digital ischemia and peripheral nerve involvement are considered more ominous manifestations that will require high dose steroids and usually cyclophosphamide. Newer biologic agents have also been reported to be beneficial in the treatment of rheumatoid vasculitis
Puechal et al. 2008.
Recently, an association of vasculitis with treatment with TNF-a inhibitors has been reported in case reports and case series. In most cases, vasculitis responded to discontinuation of the TNF-a inhibitor therapy and in some cases recurred upon reinstitution of treatment Ramos-Casals et al. 2007; Guignard et al. 2707. In most of the reported cases, only the skin was involved. However, other reports show that TNF-a inhibitors have been used successfully to treat RV Puechal et al. 2008. Whether
There is indeed an increased risk for development of vasculitis after treatment with TNF-a inhibitors and the role of these agents in the treatment of RV is an area of uncertainty.
Cachexia: Body Composition Changes
RA is associated with altered anthropometric characteristics. A low BMI - in the underweight range - is common in patients with RA, with some studies reporting a prevalence of more
Than 10% Munro and Capell 1997. A lower
BMI has been associated with radiologic progression and higher levels of disease activity Westhoff et al. 2007. This association of low BMI with adverse outcomes in RA has in fact been reported to be stronger than that of the shared epitope with the same outcomes Kaufmann et al. 2003. A lower BMI has also been associated with higher risk for disability, all cause mortality and CV associated mortality
Summers et al. 2008.
Rheumatoid cachexia is a state of loss of lean body mass and is reported to occur in up to 50% of patients Summers et al. 2008. Cachectic obesity is a condition - also commonly encountered in RA - in which loss of lean body mass is
Accompanied by gain in adipose tissue, thus maintaining "normal BMI." Both conditions are correlated with higher morbidity and mortality
Summers et al. 2008; Giles et al. 2008; 2010.
These conditions seem to be associated with the altered cytokine milieu in RA and especially with higher levels of TNF-a also called cachectin Giles et al. 2010. Excess adipose tissue in RA is reported to have a predilection for accumulation in the visceral fatty beds, thus contributing to higher prevalence of central obesity especially in men, thus increasing the risk for cardiovascular disease Giles et al. 2010. Beyond the loss in lean mass, there is evidence that muscle density is lower in RA than controls, presumably due to fatty infiltration, and possibly related to reduced number of contractile units and decreased strength Kramer et al. 2012. While the research field of anthropometry and body composition alterations in RA was a largely uncharted territory until several years ago, it has attracted more attention recently and more light should be shed soon. Evidence suggests that TNF-a inhibition may reverse some of the effects of RA on body composition and resulting cachexia
Summers et al. 2008.
Lung involvement is common in RA and may involve virtually every part of the respiratory apparatus including the upper and lower airways, the parenchyma, and the pleura. The prevalence of different forms of respiratory involvement is difficult to assess due to the frequency of subclin-ical disease, the variable sensitivity of detection methods, and the confounding influences of medications and infections. In this section, we will elaborate on the most common forms of respiratory involvement in RA that impact the most on morbidity and mortality.
Interstitial lung disease ILD is the most common and most serious form of parenchymal lung involvement in RA. It is reported to be the second highest cause of mortality in this patient population Gabriel 2008. It may remain asymptomatic and detectable only with imaging or pulmonary function testing PFT for long periods of time, but once symptoms manifest, a progressive course usually ensues, leading to early mortality Gabriel 2008. The lifetime risk for ILD has been reported to be more than 7% in subjects with RA versus less than 1% in the general population Bongartz et al. 2010. Male patients who are older at the time of RA onset and with severe articular involvement are at higher risk Anaya et al. 1995. The mortality associated with ILD in RA is nearly three times higher compared to the general population.
Once clinically manifested by cough and dyspnea, imaging generally demonstrates reticular, ground glass or honeycombing opacities, and PFT reveals restriction and a decrease in diffusion capacity.
Biopsy in RA-associated ILD - often necessary to differentiate between RA related ILD, infection, or medication toxicity - usually reveals patterns consistent with nonspecific or usual interstitial pneumonia NSIP and UIP respectively, less commonly bronchiolitis obliterans organizing pneumonia BOOP, and more rarely lymphocytic or desquamative interstitial pneumonia LIP and DIP respectively Lee et al.
2005. Between NSIP and UIP, the former is
Considered to be more responsive to immune suppression with steroids Flaherty et al. 2001.
BOOP is more dramatic in presentation with systemic features of inflammation fatigue, fever, increased inflammatory markers and, on imaging, has a characteristic appearance with patchy peripheral consolidations. It often has a less grave prognosis with favorable response to treatment with steroids.
The first line of therapy for this condition involves steroids in most of the times. In the absence of randomized clinical trials for the treatment of RA-related ILD, an inadequate response to steroids is usually followed by the addition of immunosuppressives such as azathioprine.
Pleural involvement is reported to be very common in RA often as an asymptomatic bystander. Small effusions or histologically detected pleural involvement may be present, but patients complain of symptoms rarely Balbir-Gurman et al. 2006. It frequently occurs in patients with active nodular disease and may be an incidental imaging finding or present with dyspnea.
Thoracentesis reveals an exudative effusion with typical characteristics being a low glucose level, a high LDH concentration, and the presence of giant multinucleated cells.
Therapy of the articular disease may alleviate pulmonary effusions or additional treatment with steroids or pleurodesis, and other invasive methods may be necessary.
Chronic obstructive pulmonary disease COPD/emphysema may also occur frequently in patients with RA. Difficulty in assessing its exact prevalence relates to the confounding effect of smoking and also to the fact that prevalent PFT abnormalities in patients with RA have been argued as being overall stable over time and not of significant clinical relevance Hassan et al.
1994; Fuld et al. 2003.
Apart from the above, the respiratory system may be affected in several other ways. Upper airway involvement while frequently present with diagnostic methods only on occasion will cause symptoms such as hoarseness or odynophagia Geterud et al. 1986. Laryngos-copy will assist in diagnosis and PFT may show characteristic changes in expiratory flow volumes. Obliterative bronchiolitis usually is accompanied by systemic manifestations and has a poor prognosis Devouassoux et al. 2009. Bronchiectasis is frequently encountered with CT imaging Remy-Jardin et al. 1994 but less commonly presents with symptoms. Rheumatoid nodules may be present in the lung parenchyma as mentioned earlier and when they are encountered in patients with pneumoconiosis constitute the Caplan syndrome which is only rarely recognized nowadays.
As alluded to earlier, lung involvement may be an extra-articular manifestation of RA but the differential diagnosis should always include infections, malignancies, and medication toxicity. Among the latter we will only mention here methotrexate-induced hypersensitivity acute pneumonitis, which usually has a rapid onset and is accompanied by fever and bilateral infiltrates in association with new and often severe respiratory symptoms Dawson et al. 2002. Cardiovascular Involvement
Cardiovascular involvement in RA is of particular importance, given the fact that it is recognized as the leading cause of mortality in this patient population Myasoedova et al. 2010. Recently, research has demonstrated the RA-related inflammation might be an independent risk factor for the development of atherosclerotic disease, and subclinical diastolic dysfunction Nicola et al.
2005; Arslan et al. 2006. Patients with RA are
Considered to be at increased risk for myocardial infarctions, strokes, and heart failure even after adjustment for smoking and other traditional cardiovascular risk factors Crowson et al. 2005. Medications used to treat articular disease - such as TNF-a inhibitors - may mitigate this risk Listing et al. 2008. Coronary vasculitis only rarely causes ischemic myocardial events in RA and usually only in patients with fullblown rheumatoid vasculitis and severe and active joint disease Morris et al. 1986. Current guidelines advocate annual cardiovascular risk evaluation for patients with rheumatoid arthritis and tight control of articular disease activity and conventional cardiovascular risk factors Peters
Et al. 2010.
Beyond the above, a plethora of other cardiac manifestations may be encountered in patients with RA, including pericarditis, myocarditis, and valvular disease as well as rheumatoid nodules interfering with valvular or conduction system function Voskuyl 2006.
Pericardial disease is the most common cardiovascular manifestation. In most cases, it is clinically asymptomatic and only detected by echocardiography or in autopsy series with prevalence ranges estimated to more than 30 %. Clinically evident disease is usually seen in patients with active RA, and management of the articular disease may also improve the pericardial involvement Voskuyl 2006.
Myocarditis apparently directly related to RA inflammation is increasingly recognized with MRI and PET imaging in a percentage of patients as a possible cause of heart failure HF in patients with RA Voskuyl 2006. Two major pathologic patterns are encountered: either a granulomatous pattern similar to rheumatoid nodules, or a nonspecific form Lebowitz 1963. Both forms of RA myocarditis are considered putative causes for HF in RA.
The articular inflammation of RA when active and longstanding may lead to secondary AA amyloidosis Husby 1985. Such a condition is rarely encountered today as RA arthritis medications can sufficiently render the articular inflammation into remission in the majority of patients. In the rare cases of myocardial involvement by amyloidosis, renal involvement is usually also present and a restrictive physiology may be seen on echocardiography with a characteristic sparkling pattern Voskuyl 2006.
Patients with RA may have frequent cardiac atrial and ventricular arrhythmias. Cardiovascular autonomic dysfunction, defined by decreased heart rate variability and increased QT dispersion, also reportedly increased in RA, may also contribute to the increased risk of CV disease in RA Stojanovich et al. 2007
Other Organs` Involvement
As already mentioned, neurologic involvement in RA may be encountered in the context of rheumatoid vasculitis. However, a common non-vasculitic neurological complication of RA is peripheral nerve entrapment syndrome, most typically affecting the median nerve and manifesting as carpal tunnel syndrome. Local synovitis compressing the nerve is usually the culprit and treatment of synovitis may improve symptoms, reserving surgical intervention only for resistant cases.
Muscle weakness due to disuse atrophy is encountered in patients with RA usually with active disease that interfere with exercise and deconditioning. Cachexia and loss ofmuscle density and the possible association with decreased strength is mentioned in a different section in this entry. Although autopsy series have reported low grade inflammation in muscles of RA patients, clinically evident primary inflammation is rare. In the case of clinically profound weakness, the clinician should always consider medication toxicity such as hydroxychloroquine steroid or statin-induced myopathy.
Renal involvement is also rare in rheumatoid arthritis. Biopsies have shown mild mesangiopro-liferative glomerulonephritis in a small percentage of patients. Nephrotic syndrome is only rarely encountered nowadays, given the low incidence of secondary amyloidosis in RA. NSAID-related kidney toxicity is probably the most frequent renal manifestation in patients