Systemic Lupus Erythematosus, Mixed Connective Tissue Disease, and Undifferentiated Connective Tissue Disease

Pathogenesis of Lupus Nephritis

Murine models suggest the LN is initiated by the formation of ICs, leading to activation of complement and Fcγ receptors ( Fig. 23.3 ). Indeed, the histological hallmark of LN, the “full-house” pattern of IgG, IgM, IgA, C3, C1q, and kappa and lambda light chain deposits in the kidney, support the role of ICs and complement activation in its pathogenesis. ICs form directly in the glomeruli by binding of autoantibodies to components of chromatin likely derived from the nuclear debris of apoptotic renal cells. ^, As in extrarenal SLE, genetic variants leading to increased apoptosis and decreased clearance of apoptotic debris lead to accumulation of chromatin in apoptotic nucleosomes within the kidney. IC formation within the kidney leads to activation of complement, leading to inflammation and tissue damage.

Intrarenal ICs also activate pDCs, leading to production of type 1 INF-α and induction of a variety of immune responses. Chemokines play a role in recruiting different leukocyte subsets to different parts of the kidney, such as the glomeruli or the interstitium. ^, T and B cells form lymphoid aggregates in the renal tubulointerstitium, in some cases forming germinal centers around follicular DCs. These germinal centers might play a role in persistence of renal inflammation and local generation of autoantibodies. ^, Once deposited in the mesangial matrix, ICs appear to downregulate the production of DNase I, the major renal nuclease, through incompletely understood mechanisms that might involve transcriptional interference. Decreased DNase I activity impairs clearance of apoptotic cells and leads to further and large-scale exposure of chromatin fragments. These chromatin fragments can bind directly to glomerular basement membrane and form more ICs, thereby extending the disease from the mesangial space to the glomerular capillaries. The chromatin fragments are also taken up by DCs and macrophages, where they bind to TLRs and upregulate production of metalloproteinases, which contribute to tissue injury ( Fig. 23.3 ). ^,

Once LN has been established, tissue damage can progress to chronic and irreversible stages through processes similar in many different forms of kidney disease. Focal necrosis of glomerular capillaries leads to migration of parietal epithelial cells into the glomerular tuft and production of extracellular matrix, contributing to the process of glomerulosclerosis. Breaks in the glomerular basement membrane allow leakage of plasma filtrate into the Bowman space and formation of cellular crescents that evolve into fibrocellular and fibrous crescents with glomerulosclerosis, characteristic of end-stage (class VI) LN. ^{, ,}

Classification of Lupus Glomerulonephritis

Classification of LN follows the 2003 criteria of the International Society of Nephrology/Renal Pathology Society (ISN/RPS) ( Table 23.6 ). Kidney biopsy tissue is examined by light microscopy to assess general features, cellular findings, glomerular and tubular lesions, and extent of fibrosis; immunofluorescent microscopy to determine the nature and extent of immune deposits; and electron microscopy to determine ultrastructural features and location of immune deposits within the basement membrane. LN is defined by the presence of “full-house” immune deposits. Lack of this full-house deposition calls into question the diagnosis of LN. Illustrations of class II to VI can be seen in Figs. 23.4 to 23.7 . Of note, mixed classifications occur, with features of both membranous and proliferative nephritis identified. Although not universally adopted, many pathologists report an activity index (AI) (range, 0 to 24) and chronicity index (CI) (range, 0 to 12) to quantify the degree of acute and chronic changes in a kidney biopsy for LN ^, ( eTable 23.7 ). Because the degree of active lesions (such as endocapillary proliferation, necrosis, and cellular crescents) versus chronic lesions (sclerosis, fibrous crescents, interstitial fibrosis) can play a role in treatment decisions, the ISN/RPS classification advises, but does not require, the inclusion of AI and CI in assessment of LN.

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Clinical Presentation

Although correlations often can be made between clinical presentation and histological findings in LN, the presentation of the various classes of LN can overlap, and sometimes patients with the same clinical and laboratory manifestations can have different histological patterns of glomerular involvement. Additionally, severe LN can be “silent” or present with minimal clinical and laboratory findings more characteristic of milder forms of the disease.

In general, the presentation of LN can be grouped into the following broad clinical syndromes:

• 1.

  Isolated asymptomatic hematuria and/or nonnephrotic proteinuria: generally seen in class II LN, but sometimes seen in other classes, especially if biopsy was performed after at least several months of immunosuppressive treatment.

• 2.

  Acute nephritic syndrome: defined by hematuria (microscopic or occasionally macroscopic), usually accompanied by hypertension and proteinuria ranging from mild to nephrotic. Presence of hypertension at diagnosis is suggestive of more severe disease (such as proliferative LN or advanced chronic kidney disease and scarring). Acute nephritic syndrome is commonly a manifestation of class III and IV LN. Gross (macroscopic) hematuria may be a manifestation of the acute nephritic syndrome, but it is not commonly seen in patients with SLE. When gross hematuria is present in a patient with SLE, it should raise suspicion for other causes such as renal vein thrombosis (as a complication of nephrotic syndrome or antiphospholipid antibodies), thrombotic microangiopathy, or a clotting factor deficiency (such as prothrombin deficiency). ^,

• 3.

  Nephrotic syndrome: defined by nephrotic range proteinuria, hyperlipidemia, hypoalbuminemia, and edema and may occur in isolation or associated with nephritic features. This is the most common presentation of class V LN, although class III and IV often present with nephrotic syndrome.

• 4.

  Chronic kidney disease (CKD): defined by persistent elevation of serum creatinine or reduced glomerular filtration rate (GFR). Advancing degrees of CKD can be accompanied by sequelae such as hypertension, anemia, azotemia, and metabolic bone disease. LN can occasionally present with CKD or ESKD, usually as a result of proliferative nephritis but occasionally as a result of class V LN.

Given the cumbersome nature of 24-hour urine collection, and the possible unreliability in young or noncontinent children, spot urine protein/creatinine (or urine albumin/creatinine) determination greater than 0.2 mg/mg creatinine in a first-morning urine collection is a convenient and reliable method for evaluating and following LN in children. It also shows good correlation with 24-hour urine collection.

Indications for Kidney Biopsy

The early diagnosis of LN is critical in minimizing the risk of disease progression and ESKD. The ACR has suggested the following indications for biopsy in the initial evaluation of LN: increasing serum creatinine without compelling alternative causes (such as sepsis, hypovolemia, or medication); proteinuria of 1 g or greater per 24 hours (24-hour urine or random urine protein/creatinine is acceptable); proteinuria of 0.5 g or greater per 24 hours with hematuria, 5 red blood cell (RBC) count or greater per high power field (HPF); or proteinuria of 0.5 g or greater per 24 hours with cellular casts in urine. The evidence for biopsy in children is scant; however, it is generally agreed that the clinical syndromes mentioned in the previous section are indications for biopsy in the initial evaluation of children with suspected LN. Therefore clear indications for biopsy include nephrotic syndrome, acute nephritic syndrome, and persistent elevation in creatinine. More controversial are indications for biopsy in mild, asymptomatic hematuria and/or proteinuria. These recommendations are reflected in the Single Hub and Access point for pediatric Rheumatology in Europe (SHARE) initiative where biopsy is indicated for persistent proteinuria or impaired GFR.

Given the consequences of missing and undertreating LN, and given the possibility of clinically silent LN with minimal laboratory findings and severe histology, it is the authors’ practice to have a low threshold for biopsy, which is consistent with the SHARE initiative. We recommend biopsy with any urinary abnormalities, such as urine casts, persistent proteinuria (urine protein/creatinine > 0.2 mg/mg), and/or persistent microhematuria (≥5 RBC/HPF) in addition to the more clinically overt presentations. Additionally, we recommend kidney biopsy when urine testing has not been performed prior to initiation of treatment. In a new patient with cSLE, no prior corticosteroid or other immunosuppressive therapy, normal serum creatinine, and normal urinalysis, a kidney biopsy is not indicated.

In general, a repeat biopsy should be considered in a patient with persistent or increasing proteinuria, worsening kidney function, or new development of active urine sediment. ^, A repeat biopsy also should be considered with flare of renal disease after successful treatment or if the patient fails to respond as anticipated. As defined by the Childhood Arthritis and Rheumatology Research Alliance (CARRA), a proteinuric/nephrotic renal flare is a persistent increase in the urine protein to creatinine ratio of 0.5 on spot urine after complete remission of proteinuria, or a doubling of urine protein/creatinine with a value great than 1.0 after achieving a partial response. A nonproteinuric/nephritic flare is defined as an increase or recurrence of active urine sediment (increased hematuria with or without casts), with or without an increase in proteinuria. In general, a repeat biopsy can help assess response to treatment and guide subsequent treatment. For example, persistence of active lesions might warrant a change or intensification of immunosuppression, whereas a high degree of chronic, irreversible changes might portend inevitable decline of kidney function and suggest a less aggressive approach. A repeat biopsy might also be useful in determining whether and when immunosuppression can be weaned after LN has gone into remission, though the optimal duration of treatment for LN has yet to be defined. A number of studies of urine biomarkers as an alternative to kidney biopsy in pediatric LN are ongoing.

Treatment of Lupus Nephritis

Since untreated proliferative (class III and IV) LN is associated with a high rate of mortality and ESKD, drug trials have primarily focused on treatment of proliferative LN. Early drug trials by the National Institutes of Health (NIH) established cyclophosphamide (CYC) with corticosteroids as the treatment of choice, despite higher rates of infections and amenorrhea with CYC compared with azathioprine (AZA). ^, More recently the Euro-Lupus Nephritis Trial (ELNT) demonstrated that low-dose intravenous (IV) CYC (500 mg every 2 weeks for six doses with corticosteroids followed by AZA for maintenance therapy) compared favorably with the earlier higher-dose, longer-duration regimen. ^,

Over the past decade, mycophenolate mofetil (MMF) has found increasing favor over CYC in the treatment of LN. In 2004 Contreras et al. demonstrated that, after a 6-month induction period with monthly IV CYC and steroids, maintenance therapy with either MMF or AZA was superior to long-term CYC in patient and kidney survival, with lower rates of relapse with MMF and lower rates of complications (such as amenorrhea and infections) with MMF and AZA. This study led to the abandonment of long-term CYC maintenance treatment by most practitioners. In 2005, Dooley et al. demonstrated that MMF was as effective as and safer than CYC for inducing initial remission. The MAINTAIN Nephritis Trial demonstrated that, after the ELNT regimen CYC induction, MMF and AZA were similar in efficacy for long-term maintenance in rates of relapse, disease activity, and kidney function, with lower rates of anemia and leukopenia in the MMF group. The largest randomized controlled drug trial in LN to date, the Aspreva Lupus Management Study (ALMS) study found that, in the 6-month early induction period, patients treated with corticosteroids and either MMF or IV CYC overall had similar rates of remission, although African American and Hispanic patients had a better response to MMF. In the long-term ALMS study, patients were randomized, after achieving remission, to AZA or MMF. Over 3 years of follow-up, the ALMS study demonstrated that MMF was superior to AZA in maintaining response to induction treatment and preventing relapse. A comprehensive Cochrane meta-analysis concurred that MMF was as effective as CYC for inducing remission with decreased risk of ovarian failure, and that, for maintenance therapy, the rate of relapse was lower for MMF than AZA.

In recent years there has been increasing interest in the use of biological therapies for SLE and LN. Given the role of B cells in the pathophysiology of LN, rituximab (RTX), a chimeric anti-CD20 monoclonal antibody that depletes circulating B cells, would seem to be a good candidate as alternative or adjunctive therapy in LN. The Lupus Nephritis Assessment with Rituximab (LUNAR) trial, which randomized patients with proliferative LN to receive corticosteroids and MMF plus either placebo or intermittent RTX, demonstrated no benefit in renal outcomes with the addition of RTX. However, it is possible that the use of high-dose corticosteroids and high-dose MMF left little room for improvement with the addition of RTX. The subgroup analysis of this study demonstrated that African American patients, who have a poorer prognosis, demonstrated higher partial response to RTX. Additionally, a number of observational studies report favorable results for RTX in the induction period in patients with relapsing disease or LN refractory to MMF and CYC. A recent review of 26 reports and 300 patients demonstrated combined complete and partial remission in 87% (class III), 76% (class IV), and 67% (class V) LN. Patients received one of two RTX regimens across these 26 studies, namely four weekly doses of RTX at 375 mg/m ² or two fortnightly doses of 750 mg/m ² with a maximum of 1000 mg. Patients also received a variety of concomitant treatments including CTX, MMF, and AZA. Further study is needed to determine the efficacy and optimal use of RTX.

Belimumab, a human monoclonal antibody that prevents B-cell activation (rather than depleting B cells) by blocking B lymphocyte stimulator (BLyS), was recently approved for treatment of nonrenal SLE and demonstrated improvement in disease scores when added to standard of care SLE treatment. ^, Although the belimumab trials (BLISS-52, BLISS-76) excluded patients with severe LN, a post hoc analysis of patients in the study with mild to moderate LN demonstrated greater renal improvement with belimumab added to standard treatment compared with placebo. ^, Preliminary results of a trial of belimumab in cSLE indicate that the benefit to risk profile of IV belimumab plus standard of care is generally consistent with its use in adult SLE, although final results are awaited ( https://clinicaltrials.gove/ct2/show/NCT01649765 ).

Abatacept, a fusion protein of CTLA4-Ig, blocks CD80 and CD86 on antigen-presenting cells from interacting with CD28 on T cells, thereby preventing T-cell activation. A clinical trial failed to show a benefit of abatacept over placebo when added to background immunosuppression.

Treatment of patients with mixed membranous and proliferative LN (class III/V or IV/V) generally follows the recommended treatments for proliferative disease. Few studies have examined treatment of pure class V disease because there is a lower risk of ESKD (20% at 10 years). Class V LN with low-grade proteinuria and well-preserved kidney function might only require treatment with angiotensin-converting enzyme inhibitors (ACEI) to lower proteinuria and preserve renal function. However, pure class V LN with nephrotic syndrome has a higher rate of complications, including thrombosis and cardiovascular events. Therefore immunosuppressive treatment has been recommended for class V disease with nephrotic-range proteinuria and/or decreased kidney function, although there are few randomized controlled trials defining optimal treatment for this condition. Various small studies have combined corticosteroids with another agent, such as MMF, tacrolimus (TAC), cyclosporine A (CSA), AZA, or IV CYC with beneficial results. ^{, ,}

There are few pediatric trials, mostly small observational studies, that examine the various adult treatment regimens mentioned previously in the context of pediatric LN. These studies have demonstrated beneficial effects in treatment of pediatric LN with different combinations of corticosteroids and MMF, CYC, TAC, and CSA. An important step in the standardization of treatment and future study of pediatric LN was taken with the 2012 CARRA publication of consensus guidelines for induction therapy of proliferative pediatric LN ( Fig. 23.8 ). These guidelines include three corticosteroid strategies to reflect practitioner preferences. The SHARE initiative used a nominal group method and had similar recommendations although the use of IV pulse corticosteroids was recommended only for severe disease. Maintenance therapy with MMF for pediatric proliferative LN is recommended by the SHARE initiative. For pediatric patients with pure class V disease, treatment can be adapted from the ACR adult guidelines (also endorsed by SHARE) consisting of corticosteroids and MMF or AZA, with change of treatment to IV pulse steroids and CYC for disease unresponsive to MMF or AZA. ^,

Hydroxychloroquine reduces rates of flare in SLE and incidence of renal disease and improves renal outcomes in adult studies and should be strongly recommended for use in pediatric LN. Similarly, adult studies have demonstrated the benefit of adding ACEI in reducing proteinuria and preserving kidney function, independent of the effect on hypertension.

Rashes

Most patients develop typical rashes over the course of disease (up to 85%). The archetypical malar or butterfly rash, a maculopapular rash that includes the nose and cheeks but spares the nasolabial folds ( Figs. 23.9 and 23.10 ). It is variable in intensity from a mild blush appearance to an intense erythema with a follicular or scaly appearance ( Fig. 23.11 ). It may be a diffuse lesion or have multiple satellite lesions, including the forehead and chin. This rash usually resolves without scarring. It is usually, but not necessarily, photosensitive and may be sensitive to fluorescent light as well ( Fig. 23.12 ). The lupus patient may have photosensitive annular or diffuse rashes on the limbs and chest, as well as the face. Other syndromes, including dermatomyositis, may have a photosensitive rash in the malar area ( eBox 23.2 ). However, lupus patients may have a wide range of mucocutaneous manifestations, and their presentations may differ between pediatric and adult patients.

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Discoid lupus is seen more frequently in adults either as an isolated skin disease or as part of SLE. Discoid lesions tend to occur around the eyes and ears of patients but can be distributed over the face, scalp, and body as a generalized rash ( Fig. 23.12 A to C ) . The rash tends to be hyperpigmented; however, some patients may develop hypopigmentation as well. The lesion is notable for a thick adherent scale and follicular involvement leading to hair loss at the area of the lesion. The lesions can become confluent and disfiguring and can lead to chronic alopecia in those who have scalp involvement from atrophic changes and scarring.

Subacute cutaneous lupus presents most frequently as an annular lesion associated with anti-Ro/SSA and anti-La/SSB antibodies ( Fig. 23.13 ) . Some patients have postinflammatory hyperpigmentation, which can lead to chronic scarring. This is more often seen in patients with darker pigmentation. ^{, ,} Isolated subacute cutaneous lupus erythematosus (SCLE) is also more common in adult SLE than in cSLE.

Bullous lupus erythematosus is a rare manifestation of lupus; however, it is a potentially severe lesion where extensive disease causes a diffuse skin disruption requiring care similar to patients with large burns. Bullae can also occur on mucosal areas, including the oropharynx, which can compromise the airway. Another common cutaneous phenomenon in SLE is Raynaud phenomenon (see Chapter 30 ).

Patients with cSLE may have cutaneous manifestations of vasculopathy and vasculitis. Nailfold capillaroscopy may reveal dilated vessels and loss of capillary loops similar to that seen in dermatomyositis. Livedo reticularis may be associated with the presence of antiphospholipid antibodies. Patients will also have erythema, palpable purpura ( Figs. 23.14 and Figs. 23.15 ), and ulcers or urticaria associated with lupus vasculitis or antiphospholipid syndrome (APS). Poorly controlled cutaneous vasculitis lesions can be associated with complement defects. Patients can present with petechiae and purpura because of thrombocytopenia, similar to that seen in IgA vasculitis and acute lymphocytic leukemia.

Alopecia associated with discoid lupus is rare and causes scarring. Alopecia without scarring, however, is a common finding in systemic lupus. It tends to occur at the frontotemporal line but can be more diffuse ( Fig. 23.16 ). It is a frequent symptom at disease onset and can also herald disease flares.