Interstitial pneumonia in rheumatoid arthritis (RhA) is not uncommon, but is often complicated by additional drug reactions, which can look like RhA-induced pneumonia. Most often NSIP is associated with this disease [2, 3], but these reported studies have in common a selection bias: they looked up the incidence of RhA in cases presenting with NSIP. The diversity of reaction patterns is much better reflected in studies looking up patients with RhA and lung involvement [4]. UIP was more common in this study. In my own experience, most often a mixture of reaction patterns occurred, such as UIP combined with dense lymphocytic infiltrates or LIP and UIP combined with OP or NSIP. If features of DAD occur, one should stress drug reactions with the clinicians, because many immunosuppressive drugs given in RhA and other collagen vascular diseases (CVD) can cause DAD [5–8]. Not uncommonly granulomas are present too. These are most often foreign body-type granulomas with giant cells, sometimes classical rheumatoid granulomas with palisading histiocytes, and rarely epithelioid cell granulomas [5] (Figs. 9.1, 9.2, 9.3, and 9.4). More common than granulomas is lymphocytic pneumonia combined with other patterns such as amyloid deposition (Fig. 9.5), LIP combined UIP (Figs. 9.6 and 9.7), and LIP combined OP (Fig. 9.8). Most often there is LIP pattern sometimes with fibrosis and ill-formed granulomas (Fig. 9.9). In classical rheumatoid granulomas, it is essential to exclude infectious organisms, since patients receiving immunosuppressive drugs like methotrexate and leflunomide are prone to acquire infections [8–10]. This is even more important with the new “biologicals.” As these drugs can also induce pneumonias, it is important to know these reactions. Gold salts can induce LIP or granulomatous reactions, leflunomide can induce DAD [8] (Fig. 9.10), and methotrexate can induce NSIP, LIP, and OP in the resolving phase.

The etiology of rheumatoid arthritis is still an enigma. Genetic variants for several immune regulators such as Toll receptors and interleukins may form the basis for the susceptibility to adversely react against antigens and immune complexes trapped in cartilages and by that induce an inflammatory reaction resulting in cartilage damage [11, 12]. Regulatory T cells either deficient or functionally impaired might also play an important role in rheumatoid arthritis. In addition to the genetic basis for the disease, the autoimmune reaction might be triggered by streptococcal infections, and in that respect, probably mimicry of proteins of the organism might come into play.

Localized lupus is usually seen in dermatology and rarely biopsied. Acute systemic lupus with lung manifestation is more often autopsied and rarely seen as surgical material. A variety of morphological patterns are found as hemorrhagic pneumonia, infarcts, or DAD or all mixed [13–15]. Most probably the extent of any of these reactions depends on the extent of intravascular death of neutrophils attacked by lupus autoantibodies: low numbers of dying neutrophils might release less toxic enzymes and therefore cause focal endothelial cell death and interstitial edema; proteins leak out into alveolar spaces and finally DAD with hyaline membrane formation occur (Fig. 9.11). In case of massive neutrophilic cell death, there might be massive leakage of vessel walls, and hemorrhage will occur (Fig. 9.12). In later stages, DAD will be organized, so OP is another feature found in systemic lupus (Fig. 9.13). Since the disease affects the coagulation cascade, lung infarction is a common feature of SLE. Perivascular amyloidosis is another feature in active SLE most often combined with other patterns (Fig. 9.14). Most likely amyloid deposition is associated with the deposition of immune complexes. These complexes can be large, as an immune complex may be additionally cause formation of idiopathic autoantibodies, followed by complex formation. So finally several orders of immune complex idiotypic-anti-idiotypic autoantibody complexes are formed, which are no longer soluble and therefore are deposited in the stroma. Another common finding is pleuritis. In these cases, a careful examination of the lesion is necessary as one might find LE phenomenon in the inflammatory infiltrate (Fig. 9.15). Lymphocytic infiltrations are less common in active SLE in contrast to RhA. Finally the occurrence of pulmonary hypertension with sclerosis and stenosis of pulmonary blood vessels is less well understood [16, 17] (Fig. 9.16).

The etiology of SLE is also not well understood. Autoantibodies directed against granulocytic enzymes have been shown to be secondary effects and not the cause of SLE. In a recent study in familial forms of SLE, a null mutation in the DNASE1L3 gene has been found. This finding confirms the critical role of impaired clearance of degraded DNA in SLE as a probable cause, a finding also seen in adult SLE [18]. However, given the wide range of autoantibodies found in SLE, there might be much more autoimmune mechanisms involved than anticipated [19–21].

Systemic sclerosis (SSc) usually presents with a mixture of tissue reactions, dependent on the immune phenomena present at the time of biopsy. Most often an UIP or NSIP pattern is found; some cases present as LIP with hyperplasia of BALT (Figs. 9.17, 9.18, and 9.19). Germinal centers are less common compared to Sjøgren’s syndrome. Ill-formed granulomas composed of histiocytic and/or epithelioid cells can be seen (Fig. 9.20). The distribution pattern of the interstitial pneumonia is irregular, involving peripheral as well as mid-zone areas of the lung. This is clinically helpful in separating it from UIP/IPF. Another feature helpful in the diagnosis is a vasculopathy. Medium- and small-sized arteries show a thickening of the intima and media. Within the thickened vessel wall, there is a myxoid change of the matrix. A few lymphocytes can be seen, however, no endothelial necrosis or any other sign of vasculitis. These changes can possibly be best interpreted as a consequence of immune complex deposition (Fig. 9.21). Functionally these vascular changes will cause pulmonary hypertension, which is common in systemic sclerosis [22, 23].

Genetic studies provided some new insights into SSc. Interleukins especially IL8 has an impact on lung fibrosis in SSc patients [24]. Also transforming growth factor-beta (TGF-β) and connective tissue growth factor (CTGF) received attention as essential factors in the pathogenesis of SSc. CTGF mRNA expression was observed in the fibrotic lesions; serum CTGF concentrations were significantly elevated and correlated with skin sclerosis and lung fibrosis. In an animal model, TGF-β-induced subcutaneous fibrosis and subsequent CTGF application caused persistent fibrosis. Based on these data, the authors of this study hypothesized that TGF-β induces fibrosis in the early stage, whereas CTGF acts to maintain tissue fibrosis [25]. In another study, fibrillin has been investigated. It has been demonstrated that caveolin-1 and fibrillin-1 influence storage and regulation of TGF-β and other cytokines and fibrillin-1 mutations might be responsible for a congenital form of scleroderma called stiff skin syndrome [26, 27]. In addition to tissue-resident fibroblasts, also bone marrow-derived fibroblasts and endothelial and epithelial cells undergoing epithelial-mesenchymal transition (EMT) are under the control of fibrillin. Gain-of-function and loss-of-function abnormalities of these mediators may account for the characteristic activated phenotype of SSc fibroblasts [27]. The impaired expression of the nuclear orphan receptor PPAR-γ in SSc seems to play an important role in causing uncontrolled progression of fibrosis through impaired control of fibroblast activation and differentiation [28].

Dermatomyositis rarely affects the lung. If lung involvement is present, various forms and combinations of pneumonias can occur. UIP and NSIP are the most common alterations; however, histiocytic and ill-formed epithelioid cell granulomas can be encountered in some cases in my personal experience. Lymphocytic infiltrates are quite common, most often exceeding what is seen in NSIP and better matched by LIP (Figs. 9.22 and 9.23). Vasculopathy is rare. The serosa is usually involved too; this is common in other CVDs. Polyserositis in contrast to the other CVDs cannot be diagnosed on tissues, since these serosal infiltrations are unspecific and occur in a multitude of diseases (Fig. 9.24).

Sjøgren’s syndrome (SjS) is another multisystemic collagen vascular or autoimmune disease. It affects predominantly the mucosa of salivary and lacrimal glands, but can also similarly affect the lung. The main finding is an aggressive lymphocytic infiltration into the epithelial lining of bronchi and bronchioles and a diffuse infiltration of the alveolar walls, qualifying as LIP (Fig. 9.25). In the bronchi/bronchioles, lymphoepithelial lesions occur, similar to what is seen in marginal zone lymphomas. The epithelial layer is disrupted, which later on is repaired and can present as OP (Fig. 9.26). The lymphocytic infiltration is polyclonal and composed of T and B lymphocytes. Lymph follicles are well formed and will show activated germinal centers. Other types of interstitial pneumonias can be associated to LIP, even UIP can occur, usually in the form of UIP-LIP mixed pattern (Figs. 9.27 and 9.28).

As in SSc interleukins are playing an important role in Sjøgren’s syndrome too. IL12 overexpressing transgenic mice developed bronchial and alveolar abnormalities such as lymphocytic infiltrates around the bronchi, cell proliferation in the alveolar septa, and increased interstitial and alveolar macrophages, strikingly similar to those found in the lungs of Sjøgren’s patients. There were also fourfold higher numbers of natural killer cells. A new mouse model highlights the role of IL12 in the initiation of Sjøgren’s syndrome [29]. Rangel-Moreno studied the hyperplasia of BALT in patients with pulmonary involvement in rheumatoid arthritis and Sjøgren’s syndrome. Increased expression of CXCL13 and CCL21, as well as B-cell activating factor of the TNF family (BAFF), ICOS ligand, and lymphotoxin, correlated with BALT hyperplasia. The presence of BALT hyperplasia correlated also with tissue damage in the lungs of these patients [30]. In a recent investigation, genes have been identified related to one of the major symptoms of Sjøgren’s syndrome, namely, the immunological attack of salivary and lacrimal glands resulting in the loss of acinar cell tissue and function, leading to stomatitis sicca and keratoconjunctivitis sicca. One gene lying on chromosome 1 (autoimmune exocrinopathy 2, Aec2) and the second on chromosome 3 (autoimmune exocrinopathy 1, Aec1) have been shown to be necessary and sufficient to replicate SjS-like disease in C57BL/6 mice. Aec2 lies distal to the centromere. This chromosomal region contains several sets of genes known to correlate with various immunopathological features of SjS. One gene in particular, tumor necrosis factor (ligand) superfamily member 4 (or Ox40 ligand), encoding a product whose biological functions correlate with both physiological homeostasis and immune regulations, could be a potential candidate SjS susceptibility gene [31]. Although many open questions remain, this mouse model opens the way to better understand this autoimmune disease and also will serve to study the mechanisms, which are responsible for the common development into MALT lymphomas.

Mixed CVD cannot be diagnosed with certainty. The combination of features of two different CVD makes it almost impossible to come up with an etiologic suggestion or proposal. Depending on the features of the single CVD, morphologic mixtures can be found. For example, mixed Sjøgren’s-lupus CVD can either have dominant features of Sjøgren’s syndrome or systemic lupus [32]. However, general features suggestive of CVD are usually present: a combination of different features of interstitial pneumonias with lymphocytic infiltrations, hemorrhage, etc. (Fig. 9.29).

Goodpasture syndrome is an autoimmune disease not related to CVD. The cause has been identified recently: by a mimicry against bacterial proteins, cross-reacting autoantibodies are formed, which bind to the α-3-chain of collagen IV causing disruption and hemorrhage by complement activation (most often the alternate pathway) [33, 34]. There are still unexplained features such as why collagen IV in glomerular, alveolar, and alveolar capillary basement membranes is attacked, but not those in other organs.

Macroscopically there are scattered areas of hemorrhage corresponding to the clinical picture of alveolar hemorrhage (Fig. 9.30). The major histologic finding is alveolar hemorrhage without infiltrating leukocytes (Figs. 9.31 and 9.32). Most important is the finding of hemosiderin-laden alveolar macrophages in alveoli and in the interstitium, pointing to previous episodes of hemorrhage. In rare cases with massive hemorrhage, hyaline membranes may be focally encountered (Fig. 9.33), which will undergo organization and result in focal scars. Depending on the duration of the disease, finally septal fibrosis results [35]. In all cases, the deposition of autoantibodies to the constituents of the basal lamina needs to be proven. These cytotoxic autoantibodies (immune reaction type II) can be demonstrated as linear deposits along the alveolar basement membrane as well as that of capillaries (Fig. 9.34). These autoantibodies activate the complement cascade without any additional help from leukocytes; in my experience, most often the alternative complement pathway is activated.