Systemic Lupus Erythematosus Management

Evaluation

Specialist Referral 

It is essential to establish a good working relationship among the primary care physician, non-lupus specialist (eg general internist or pediatrician), lupus specialist (eg rheumatologist), nurse, pharmacist, other healthcare providers, the patient, and his/her family. A team approach, including collaborative care between rheumatologists and other appropriate specialists whenever possible, will allow for earlier identification of disease flares and medication toxicity. 

The patient will initially present to a primary care physician or non-lupus specialist who is responsible for recognizing the signs and symptoms of systemic lupus erythematosus in their patients, making an initial diagnosis, treating and monitoring patients with mild disease, and referring the patient to a rheumatologist or other lupus specialist (eg nephrologist) and participating in further systemic lupus erythematosus diagnosis, management, and monitoring of patients with moderate to severe disease.

The lupus specialist is an integral part of the medical team managing a systemic lupus erythematosus patient. Referral to a lupus specialist especially a rheumatologist is indicated for confirmation of the diagnosis, formulation of a management plan for the patient, periodic evaluation of disease activity and severity, management of uncontrolled disease and complications, management of organ involvement or life-threatening diseases, prevention and/or management of treatment toxicities, and in special situations (eg pregnancy, antiphospholipid syndrome, concomitant infection, and surgery). 

Multidisciplinary care involves the referral of systemic lupus erythematosus patients to a psychologist, psychiatrist, physical and/or occupational therapist, ophthalmologist, dermatologist, cardiologist, orthopedic surgeon, and other specialists when necessary.

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Principles of Therapy

Patients require individualized therapy depending on disease manifestations, activity and severity, side effects of treatment, risk for progressive organ damage, and presence of comorbidities. When systemic lupus erythematosus involves multiple organ systems at presentation or during a flare, treatment should address all affected manifestations while prioritizing those at highest risk of irreversible organ damage. Organ- or life-threatening systemic lupus erythematosus requires prompt, intensive treatment, typically with pulse or high-dose glucocorticoids and immunosuppressive therapy. Combination regimens may be initiated when rapid disease control is needed, with treatment selection guided by the clinical scenario and patient preferences. For ongoing systemic lupus erythematosus disease activity in any organ system refractory to initial therapy, treatment escalation is recommended. If clinical or serologic findings suggest a coexisting disease process or overlap with systemic lupus erythematosus, treatment should be modified as appropriate based on the predominant condition and in consultation with the relevant specialists.

Goals of Therapy  

The goals of therapy are to achieve and maintain systemic lupus erythematosus remission or low lupus disease activity, prevent progression of chronic kidney disease and flares, reduce systemic lupus erythematosus-related morbidity and mortality, and minimize treatment-related toxicities. Complete remission is the sustained absence of clinical disease activity (SLEDAI-2K = 0) without the use of corticosteroids and immunosuppressants. Low disease activity is defined as SLEDAI-2K ≤4 (without activity in major organ systems or new/worsening symptoms), PGA ≤1, corticosteroid use of ≤5 mg/day of Prednisone, and well-tolerated immunosuppressants in stable doses. Additional goals include preventing serious organ damage that adversely affects function or life span and allowing the patient to have long-term survival and good quality of life without major exacerbations.

Pharmacological therapy

Anti-inflammatory Agents

Corticosteroids

Glucocorticoids should be used mainly for the prompt initial control of immune-mediated inflammation and, when necessary, during flares, using the lowest effective dose and shortest duration necessary, with tapering initiated as soon as possible.

Oral Corticosteroids

Corticosteroids decrease inflammation by suppressing the immune system. They decrease lymphocyte volume and activity, polymorphonuclear leukocyte migration, and capillary permeability. They are used as initial therapy for severe lupus erythematosus or lupus vasculitis, and for acute flare. Patients with mild systemic lupus erythematosus do not normally require the use of systemic corticosteroids, but there are patients whose quality of life is not improved if not given low-dose corticosteroids. Patients in remission for with low disease activity should be maintained with the lowest possible glucocorticoid dose.  Low-dose corticosteroids may be added to Hydroxychloroquine for fatigue and fever. High-dose corticosteroids are necessary for the refractory manifestations of systemic lupus erythematosus and for severe organ involvement especially central nervous system (CNS), renal, and hematologic manifestations. High-dose corticosteroids showed improved survival in patients with severe forms of systemic lupus erythematosus nephritis, may also be useful in severe, life-threatening thrombocytopenia, and hemolytic anemia, and in pleuritis or pericarditis. In patients with stable, controlled systemic lupus erythematosus receiving Prednisone >5 mg/day, tapering to ≤5 mg/day, preferably to discontinuation, is recommended within 6 months.

Corticosteroid use should be ≤5 mg/day (Prednisone equivalent) during chronic maintenance therapy and tapered as soon as the desired response is achieved (control of inflammatory manifestations) to minimize toxicity; in patients with sustained remission on Prednisone ≤5 mg/day, a slow taper toward discontinuation may be considered. Tapering or withdrawing corticosteroids may be hastened with the prompt initiation of immunosuppressants. Initiation or escalation of immunosuppressive therapy may be considered if unable to taper Prednisone to ≤5 mg/day. High doses over periods of >2–3 weeks suppress adrenal function.

Topical Corticosteroids

Topical glucocorticoids are helpful for mild cutaneous involvement or discoid lesions, especially on the scalp. Generally, avoid the use of fluorinated glucocorticoids on the face except for a few days if with severe flare. Low-potency topical glucocorticoids may be used for active facial lesions for a limited duration. Moderate- or higher-potency topical glucocorticoids can be used for non-facial and non-intertriginous areas. High-potency topical glucocorticoids should be reserved for short-term use only because of the risk of skin atrophy.

Parenteral Corticosteroids

Pulse therapy with IV corticosteroids, with or without immunosuppressive therapy, can be given to patients with severe organ or life-threatening manifestations. IV pulse dosing of Methylprednisolone gives an immediate therapeutic effect and allows the initiation of oral corticosteroids at a lower dose. In patients with organ- or life-threatening systemic lupus erythematosus flares, pulse Methylprednisolone treatment (eg 250-1,000 mg for 1-3 days) followed by an oral glucocorticoid taper may be considered over a high-dose oral glucocorticoid taper without pulse treatment.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  

NSAIDs work by inhibiting inflammatory reactions and pain by decreasing prostaglandin synthesis. They provide symptomatic relief of fever, arthritis, and mild serositis (ie control symptoms in mild non-renal lupus). They are used in caution in patients with lupus nephritis or hypertension. Systemic lupus erythematosus patients also have high incidence of NSAID-induced hepatotoxicity.

Disease-Modifying Anti-Rheumatic Drug (DMARD)

Hydroxychloroquine

Hydroxychloroquine is a 4-aminoquinolone antimalarial that has immunomodulatory and anti-inflammatory effects in the treatment of systemic lupus erythematosus. It works by inhibiting the chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. It is recommended for all systemic lupus erythematosus patients unless intolerant or contraindicated. It is used for skin and joint manifestations and is useful for patients with a skin disease that is unresponsive to topical corticosteroids and in patients with arthritis that do not respond to NSAIDs. It is recommended as background treatment for class III/IV systemic lupus erythematosus patients with nephritis. Patients with continuing treatment with Hydroxychloroquine showed less renal damage as compared to those on placebo. It is also used for preventing flares and sustaining remission, reducing cardiovascular risk, recurrent infection, and other constitutional symptoms. The use of short courses of higher doses of therapy (5-6.5 mg/kg/day) may be necessary at treatment initiation or to maintain disease control. A long-term average dose goal of ≤5 mg/kg/day may be considered to minimize retinal toxicity. Treatment may be continued indefinitely, including in patients with sustained remission.

Immunosuppressants

These agents act as immunosuppressive, cytotoxic, and anti-inflammatory agents. Early use of conventional and/or biologic immunosuppressive therapies is encouraged in patients with ongoing systemic lupus erythematosus activity to attain control of systemic lupus erythematosus inflammation, achieve remission or low disease activity, lessen systemic lupus erythematosus-related morbidity and mortality, and reduce glucocorticoid-related toxicities. The choice of immunosuppressant will depend on the nature and severity of disease manifestation. The addition of immunosuppressants is considered in patients intolerant or unresponsive to Hydroxychloroquine therapy (with or without corticosteroids) or unable to decrease corticosteroid doses below that acceptable for chronic use. Immunosuppressants can be included in the initial treatment of organ- or life-threatening systemic lupus erythematosus, wherein an initial course of high-intensity immunosuppressive therapy is given, followed by a longer course of less intensive treatment to consolidate the patient’s response and prevent relapses. In the treatment of severe CNS and severe glomerulonephritis, thrombocytopenia, and hemolytic anemia, high-dose glucocorticoids and immunosuppressants are used. Concomitant use with corticosteroids allows lower doses of immunosuppressants. In patients with systemic lupus erythematosus who have sustained clinical remission or low disease activity, tapering of immunosuppressive therapy after 3-5 years may be considered, with the goal of eventual discontinuation.

Conventional Immunosuppressive Therapy
 
Azathioprine

Azathioprine antagonizes purine metabolism and inhibits the synthesis of DNA, RNA, and proteins. It may decrease the proliferation of immune cells resulting in lower autoimmune activity. 

It is used for mild to moderate systemic lupus erythematosus-related organ involvements (ie renal, neurological, hematological) and can also prevent flares. It may be used as the initial immunosuppressant for systemic lupus erythematosus nephritis. 

Calcineurin Inhibitors

Example drugs: Ciclosporin, Tacrolimus, Voclosporin

Calcineurin inhibitors can be considered in patients with moderate to severe systemic lupus erythematosus with arthritis, cutaneous disease, cytopenia, serositis, or vasculitis if Hydroxychloroquine treatment is insufficient. Topical calcineurin inhibitors can be used for cutaneous lupus of the face without restriction or no limit to duration of use. Calcineurin inhibitors can also be considered in the subsequent treatment of pure class V nephritis. 

Cyclophosphamide

Cyclophosphamide is an alkylating agent that may involve cross-linking of DNA which may interfere with the growth of normal and neoplastic cells. 

It is used as an initial immunosuppressant for severe systemic lupus erythematosus nephritis. Concomitant use with Prednisone is the standard treatment for lupus nephritis as it helps preserve renal function. It is also useful for induction therapy in severe organ- or life-threatening systemic lupus erythematosus (eg severe CNS, cardiopulmonary, or renal involvement) and as rescue therapy for non-major organ manifestations unresponsive to other immunosuppressants. It also prevents lupus flares. 

Methotrexate

Methotrexate works by blocking purine synthesis and increasing the anti-inflammatory adenosine concentration at the sites of inflammation. 

It is used for mild to moderate non-renal systemic lupus erythematosus and it can also prevent flares. It is often used as the initial immunosuppressant for musculoskeletal (eg severe arthritis) and cutaneous symptoms uncontrolled with corticosteroids and Hydroxychloroquine. Supplementation with folate is advised to decrease treatment-associated adverse effects and toxicity.

Mycophenolic Acid Analogs

Mycophenolate mofetil and enteric-coated Mycophenolate sodium are prodrug formulations of Mycophenolic acid, the active immunosuppressive drug. Mycophenolic acid is a reversible inhibitor of inosine monophosphate dehydrogenase which is the rate-limiting enzyme in the de novo purine synthesis. 

It is effective for both renal and non-renal lupus and certain neuropsychiatric diseases. It is used for moderate to severe non-renal systemic lupus erythematosus and can also prevent flares. It is recommended as induction and maintenance therapy for patients with lupus nephritis and has shown better results (less adverse effects and infections) as compared to an intravenous Cyclophosphamide.

Biologic Immunosuppressive Therapy

Consider giving monoclonal antibodies to patients who are unresponsive to treatment with corticosteroids and with maximum tolerable doses of immunosuppressants. They may also be considered in patients with intolerance or contraindications to standard treatment and/or in refractory diseases.
 
Anifrolumab

Anifrolumab is a human IgG1 kappa monoclonal antibody that inhibits signaling of type I interferon by binding to subunit 1 of the type I interferon receptor resulting in the improvement of systemic lupus erythematosus symptoms. It is used for the treatment of moderate to severe systemic lupus erythematosus in adult patients who are receiving standard therapy (eg NSAIDs, corticosteroids, antimalarials, and/or conventional immunosuppressants [Azathioprine, Methotrexate, or Mycophenolate]). It is not recommended for patients with severe active CNS lupus or severe active lupus nephritis.
 
Belimumab

Belimumab is a human monoclonal antibody that binds to a soluble B-lymphocyte stimulator (BLyS/B- cell activating factor [BAFF]) to reduce disease activity. It is used as an add-on therapy for patients with active, autoantibody positive systemic lupus erythematosus with a high degree of disease activity (eg positive anti-dsDNA and low complement) despite standard therapy (Hydroxychloroquine and corticosteroid combinations with or without immunosuppressants). It may be considered as an add-on therapy to extrarenal disease that is persistently active or flaring, or to patients with frequent relapses and/or residual disease activity preventing corticosteroid tapering. 

Studies have shown that patients on Belimumab therapy experienced a reduced risk of severe flares, improved health-related quality of life, and reduced steroid use as compared to those on placebo. It is not recommended for patients with severe active CNS lupus. 

Obinutuzumab  

Obinutuzumab is a CD20-directed cytolytic monoclonal antibody indicated for active lupus nephritis in individuals receiving standard therapy. It was evaluated in a phase 3 trial of adults with active systemic lupus erythematosus without proliferative or membranous lupus nephritis and appears to be effective when used off-label for systemic lupus erythematosus along with standard therapy.

Rituximab

Rituximab is a biologic agent and chimeric monoclonal antibody to CD20 antigen which regulates cell cycle initiation. It is used as rescue therapy for systemic lupus erythematosus patients with organ-threatening disease refractory or with intolerance or contraindications to standard immunosuppressive therapy. 

Intravenous Immunoglobulin (IVIg)

IVIg works by neutralizing circulating myelin antibodies through anti-idiotypic antibodies, therefore down-regulates proinflammatory cytokines, including interferon-gamma; blocks receptors on macrophages, suppresses inducer T and B cells, and augments suppressor T cells; and blocks complement cascade, promotes remyelination and may increase colony stimulating factor lgG. 

It is used in serious systemic lupus erythematosus flares and refractory severe lupus. It may be considered in the acute phase of lupus thrombocytopenia if there is an inadequate response to high-dose corticosteroids or to prevent infectious complications from corticosteroid therapy. 

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• Mycophenolate or low-dose IV Cyclophosphamide with Belimumab
• Mycophenolate with a calcineurin inhibitor (Voclosporin or Tacrolimus)
• Mycophenolate with Obinutuzumab

For rapidly progressive glomerulonephritis, a short course (6-7 monthly pulses) of high-dose IV Cyclophosphamide plus pulse IV Methylprednisolone can also be considered. Following a renal response, maintenance treatment should generally continue for at least 3 years, based on the initial regimen. Azathioprine or Mycophenolate are the preferred maintenance therapies, particularly for patients given Ciclosporin as the initial treatment agent. Azathioprine or Mycophenolate should replace Cyclophosphamide for those initially treated with Cyclophosphamide, alone or in combination with Belimumab. Patients initially treated with Mycophenolate alone or in combination with Belimumab, a calcineurin inhibitor, or Obinutuzumab should continue on these drugs. Maintenance treatment with a calcineurin inhibitor may also be considered in class V lupus nephritis at its lowest effective dose. In patients with sustained complete renal response, gradual withdrawal of immunosuppressive and/or biologic therapy may be considered after approximately 3 years of treatment, taking the risk of flare into account. For refractory disease, patient adherence should be assessed first; if disease activity persists despite adequate adherence, Mycophenolate, Ciclosporin, or calcineurin inhibitors may be used as monotherapy or combination therapy. Studies showed that Rituximab, Obinutuzumab, Belimumab/Mycophenolate, Belimumab/Rituximab, and high-dose IVIg are viable alternative treatment options. Patients with persistently active or relapsing disease may benefit from switching among available immunosuppressive and/or biologic therapies, with specialist referral recommended to regularly assess risk factors for chronic kidney disease progression.
 
Neuropsychiatric Systemic Lupus Erythematosus (NPSLE)

Manifestations indicating an inflammatory process are treated with corticosteroids and/or immunosuppressants while atherothrombotic or antiphospholipid-related manifestations are treated with antiplatelets or anticoagulants. For active lupus optic neuritis, lupus acute confusional state, or active lupus mononeuritis multiplex, initial treatment with pulse or high-dose glucocorticoid taper plus immunosuppressive therapy with IV Cyclophosphamide, Mycophenolic acid analogs, or anti-CD20 therapy (eg Rituximab, Obinutuzumab) may be considered. For active lupus myelitis, initial treatment with pulse or high-dose glucocorticoid and IV Cyclophosphamide may be considered. For active lupus psychosis, antipsychotic therapy plus glucocorticoid, IV Cyclophosphamide, Mycophenolic acid analogs, or anti-CD20 therapy may be considered. For seizures attributed to active systemic lupus erythematosus, anti-seizure medication plus glucocorticoid, Azathioprine, Cyclophosphamide, Mycophenolic acid analogs, and/or anti-CD20 therapy may be considered. Patients found to have NPSLE should be referred to a team of psychiatrists, psychologists, neurologists, and rheumatologists. 
 
Skin Disease  

The initial management for cutaneous lupus rash includes the use of topical agents (glucocorticoids and/or calcineurin inhibitors), antimalarials (Hydroxychloroquine, Quinacrine), a course of intralesional glucocorticoid and/or a brief, limited course of systemic corticosteroids. There is no significant difference in the topical options used across the various cutaneous lupus subtypes, except in lupus panniculitis, where topical glucocorticoids are unlikely to reach the fat, the primary area of inflammation. If unresponsive to initial management, for acute, subacute, and chronic cutaneous lupus, mild disease may be treated by modifying antimalarial therapy by adding Quinacrine or switching from Hydroxychloroquine to Chloroquine. For moderate-to-severe disease, add Methotrexate, Mycophenolic acid analogs, Anifrolumab, and/or Belimumab. Moderate-to-severe cutaneous lupus that is also refractory to immunosuppressive therapies may be treated by adding or substituting Lenalidomide. For bullous lupus erythematosus, Dapsone should initially be added for mild disease rather than initiating glucocorticoids, while Azathioprine, Methotrexate, Mycophenolic acid analogs, and/or anti-CD20 therapy may be added for moderate-to-severe disease. For Chilblain lupus, add Pentoxifylline, phosphodiesterase type 5 (PDE5) inhibitors (eg Sildenafil, Tadalafil), and/or calcium channel blockers (eg Nifedipine). For leukocytoclastic vasculitis (mild cutaneous vasculitis), add Dapsone or Colchicine before immunosuppressive therapies, including oral glucocorticoids.
 
Hematological Disease  

Lupus thrombocytopenia and autoimmune hemolytic anemia can be acutely treated with moderate to high doses of corticosteroids (including intravenous pulse dosing of Methylprednisolone) in combination with immunosuppressants and/or IVIg. For chronic asymptomatic thrombocytopenia, a glucocorticoid may be initiated with additional therapy, including Azathioprine, calcineurin inhibitor, Mycophenolic acid analogs, Belimumab, anti-CD20 agents, and/or IVIg. For symptomatic thrombocytopenia or symptomatic autoimmune hemolytic anemia, a glucocorticoid may be initiated with the addition of IVIg and/or anti-CD20 therapy. Azathioprine, Mycophenolate, or Ciclosporin can be used for maintenance therapy. Refractory patients can be given Rituximab or Cyclophosphamide. 

Musculoskeletal Disease  

Acute or recurrent inflammatory arthritis in people with systemic lupus erythematosus may be initially managed with an NSAID or a short course of oral glucocorticoids while awaiting the therapeutic effects of recommended long-term treatments. Patients with persistent or recurrent active systemic lupus erythematosus arthritis on Hydroxychloroquine, regardless of prior or current NSAID or short-term glucocorticoid use, may be treated initially with Methotrexate, Mycophenolic acid analogs, or Azathioprine, with early addition of or substitution with Anifrolumab or Belimumab if disease activity remains inadequately controlled.  

Pleuropericarditis  

Initial management of lupus pleuropericarditis may include NSAIDs, Colchicine, or their combination, with a low threshold for escalating to glucocorticoid therapy as needed. In patients with ongoing or recurrent lupus pleuropericarditis despite Hydroxychloroquine, NSAIDs, Colchicine, and/or glucocorticoid therapy, escalation to immunosuppressive therapies (eg Azathioprine, Mycophenolic acid analogs, Anifrolumab, or Belimumab) may be warranted.  

Systemic Vasculitis  

For active SLE-related vasculitis, treatment may be initiated with pulse or high-dose glucocorticoids followed by tapering and combined with immunosuppressive therapy (eg Azathioprine, IV Cyclophosphamide, Mycophenolic acid analogs, Anifrolumab, Belimumab, or anti-CD20 therapy). Severe vasculitis may warrant initial treatment with IV Cyclophosphamide or anti-CD20 therapy. For life-threatening vasculitis (eg diffuse alveolar hemorrhage or mesenteric vasculitis), plasma exchange and/or IVIg may be added to pulse or high-dose glucocorticoid and immunosuppressive therapy. 

Nonpharmacological

Patient Education

Patients should be provided with information, counseling, and support. Shared decision-making and individualized treatment based on patient preferences and clinical status can improve adherence and outcomes. It is important to involve all the family members in the counseling regarding the disease since the family must have a thorough understanding of the disease, its potential severity, and the complications of the disease and treatment.  

Patients must learn to cope with and monitor the disease. They should be able to distinguish the signs and symptoms that may precede a disease flare and consult with the physician immediately. Advise patients to join other systemic lupus erythematosus patients in support groups. Educate all patients regarding the prevention of cardiovascular complications and possible complications from unplanned pregnancy, poor compliance, recreational drug use, and infection.  

Patients must be advised to wear clothing with long sleeves, use an umbrella or sunscreen lotion and refrain from sunbathing to prevent exacerbation of dermatologic symptoms and minimize the risk of systemic lupus erythematosus flare. Sunscreens should block both UVB and UVA; use sunscreen with at least a sun-protection factor (SPF) of 15-75 to prevent dermal or systemic disease flares upon exposure to ultraviolet light. SPF ≥70 chemical sunscreens or SPF ≥50 physical blocker sunscreens are recommended; physical blocker sunscreens may be preferred in allergy-prone individuals. 

The patient’s comorbidities should be managed; blood pressure, glucose, and lipid levels should be assessed and managed appropriately. Encourage patients to maintain a healthy lifestyle with regular exercise to maintain appropriate weight and bone density. Advise patients on sleep hygiene and that fatigue and stress are associated with disease flares. Smoking cessation is recommended. Patients must have an appropriate balanced diet to prevent obesity, osteoporosis, and dyslipidemia. Patients on corticosteroids should have a no-added-salt (salt intake <5 g/day), low-fat, and calcium-sufficient diet.  

The patient should also be counseled regarding reproductive health. Contraception is important during the active phase of the disease, and no estrogen-containing methods should be used if with active disease or with positive antiphospholipid antibodies. Attempt conception after stable or low disease activity on pregnancy-compatible medications for 4-6 months. It is also important to avoid pregnancy if with significant organ damage. Avoid hormone replacement therapy during menopause if with active disease or with positive antiphospholipid antibodies.  

Immunization should be updated for all patients. Patients should have appropriate immunizations to prevent infections (eg influenza, pneumococcus, recombinant varicella zoster virus [VZV], coronavirus disease 2019 [COVID-19], herpes zoster virus, respiratory syncytial virus [RSV], hepatitis B virus [HBV], and human papillomavirus). Immunizations should preferably be given before initiation of immunosuppressant therapy or during remission or low disease activity.  

Exposure to immunosuppressive drugs used in systemic lupus erythematosus may predispose patients to infection. Therefore, advise patients to seek medical help when they have fever. Antibiotic prophylaxis should be provided for all dental, genitourinary, and other invasive procedures for patients at high risk of infections (eg patients with valvular abnormalities or on immunosuppressive therapy).  

Patients should regularly undergo gynecologic assessments, dental care, and bone health assessments while taking corticosteroids, and ophthalmologic examination while taking long-term Hydroxychloroquine. People with systemic lupus erythematosus should keep up to date with recommended cancer screening tests appropriate for their age, sex, and individual risk factors. Lastly, psychological support and interventions may also be necessary.

Plasma Exchange or Plasmapheresis  

In plasma exchange or plasmapheresis, high molecular weight substances involved in systemic lupus erythematosus pathogenesis undergo extracorporeal removal followed by return or exchange of blood plasma or components. It is an alternative therapeutic modality in select patients with acute life-threatening manifestations, rare complications, and severe refractory disease, in particular lupus nephritis and thrombotic thrombocytopenic purpura.

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