Skip to main content
NCBI home page
NIHPA Author Manuscripts logoLink to NIHPA Author Manuscripts
. Author manuscript; available in PMC: 2023 Jun 14.
Published in final edited form as: Rheum Dis Clin North Am. 2021 Feb 25;47(2):215–228. doi: 10.1016/j.rdc.2020.12.004

The Categorization of Pain in Systemic Lupus Erythematosus

David S Pisetsky 1,2, Amanda M Eudy 1, Megan EB Clowse 1, Jennifer L Rogers 1
PMCID: PMC10262682  NIHMSID: NIHMS1896986  PMID: 33781491

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by immunological disturbances and diverse symptoms that vary in pattern and severity among patients (1, 2). These disturbances are highly interconnected and underlie many of the clinical and laboratory findings of SLE, including the prominent expression of antinuclear antibodies (ANA) (3). In view of the unequivocal evidence of immune cell disturbance in SLE, investigators have tended to view disease pathogenesis as well as disease manifestations primarily in terms of immunology. Since current technologies are providing a more detailed picture of cellular abnormalities than ever before possible, investigative interest in this area has surged (4).

While characterizing immune abnormalities is eminently appropriate for an autoimmune disease, such a focus may not adequately incorporate the patient perspective and the wide range of symptoms of SLE that can impact quality of life. SLE is a disease of tissue inflammation and injury. It is also a very painful disease in which pain can dominate the lived experience of the patient (5). Furthermore, pain in SLE can occur in the context of other symptoms such as fatigue which can impair quality of life beyond the consequences of inflammatory injury of the tissues (6–9).

For the patient, pain is often the symptom that brings them to the physician, with pain relief the proximate goal of therapy. For the physician or other provider evaluating such a patient, the challenge is to understand the origin of the pain, assess its relationship to inflammation and develop a treatment plan to lessen its impact. In the treatment of SLE, pain management is a particular challenge since the relationship of pain to inflammation is often obscure, with immunomodulatory therapy frequently unsuccessful. As a result, patients may experience inadequate symptom relief, leading to dissatisfaction with the medical encounter. Discordancy between patients and providers in the assessment of the basis of symptoms can, unfortunately, complicate communication and prevent the establishment of an effective therapeutic relationship (10–12).

In our unit, we have been exploring a new approach to the management of pain in SLE which we hope will improve overall patient care. This approach is based on the division of signs and symptoms of SLE into two broad categories that are termed Type 1 and Type 2; in view of their temporal variation, both types can be assessed at the time of each medical visit (13, 14). Type 1 manifestations are the classic signs and symptoms of SLE that are, in general, immunologically mediated. These manifestations include nephritis, inflammatory arthritis, rash and serositis. Type 2 manifestations include pain (especially fibromyalgia), fatigue, depression sleep disturbance and perceived cognitive dysfunction.

In this article, we will review manifestations of SLE that are painful and then discuss in more detail the application of the Type 1 and Type 2 categorization to patient care. As this discussion proceeds, it is important to note that we consider both Type 1 and Type 2 symptoms as manifestations of underlying disease pathogenesis in SLE, even if the link between certain symptoms and immune cell abnormalities may be obscure at the present time.

MUSCULOSKELETAL PAIN

Table 1 lists the cause of pain attributable to the musculoskeletal system. These manifestations encompass both inflammation and damage as well as symptoms that would be categorized as Type 2 symptoms.

TABLE 1.

Sources of Musculoskeletal Pain

Condition Mechanism
Arthritis Activity
Myositis Activity
Avascular necrosis Damage
Fracture Damage
Osteoarthritis  ?
Fibromyalgia Type 2
Open in a new tab

Arthritis

The importance of arthritis as a manifestation of SLE has grown especially in the setting of clinical trials for new agents to treat this disease. In the development path, the usual first step is the assessment of the ensemble of manifestations known as non-renal SLE which primarily involve musculoskeletal and mucocutaneous manifestations (15). Unlike nephritis which has been extensively investigated in animal models of disease and has a well-validated disease mechanism (i.e., immune complex deposition), arthritis and related musculoskeletal manifestations have lacked a clear model or experimental framework to elucidate mechanisms.

According to classical concepts of arthritis in SLE, patients can display three distinct patterns of joint involvement: 1) a symmetric polyarthritis involving primarily the small joints, with prominent involvement of the fingers and wrists; 2) a non-erosive deforming arthritis, termed Jaccoud’s arthropathy, characterized by reducible ulnar deviation and swan neck deformities due to ligamentous and joint capsule laxity; and 3) an overlap between SLE and RA that is characterized by serological disturbances similar to those of RA (i.e., anti-CCP and rheumatoid factor) (16, 17). This overlap condition has sometimes been called “rhupus.” Table 2 presents definitions of joint involvement in SLE used to measure for assessing classification or disease activity (18–20).

TABLE 2.

Definitions of Arthritis or Joint Involvement in SLE

SLICC Criteria for Disease Classification
Synovitis involving two or more joints, characterized by swelling or effusion OR tenderness of two more joints and 30 minutes of morning stiffness
2019 ACR-EULAR Criteria for Disease Classification
EITHER 1) synovitis involving two or more joints characterized by swelling or effusion OR 2) tenderness in two or more joints and at least 30 minutes of morning stiffness
SLEDAI
More than two joints with pain and signs of inflammation (i.e., tenderness, swelling or effusion)
Open in a new tab

According to the older literature, the small joint form of arthritis is marked by pain out of proportion to the findings on physical exam and, while joint tenderness can be elicited, swelling has been considered to be mild. Since plain radiographs do not show evidence of erosion, patient reports of pain and tenderness have represented the most substantial evidence of synovitis.

More recent studies are redefining the nature of arthritis in SLE, positing greater similarity to RA than historically thought. One possibility for the changing perspective relates to changes in the nature of synovitis in RA which is the prime example of an inflammatory arthritis with which others are compared. As many clinicians can attest, RA now appears to be a less severe condition than before; this situation perhaps reflects earlier recognition and treatment with more effective disease modifying anti-rheumatic drugs (DMARDs) (21). In RA at present, synovitis appears less prominent and both erosion and deformity are markedly attenuated. In the care of patients with RA, clinicians have adapted to a picture of a much less severe disease, interpreting lesser degrees of synovitis as, nevertheless, clinically significant.

Now that clinicians are accustomed to assessing more limited joint findings as evidence of active RA, they are perhaps paying more attention to synovitis in SLE. As such, the same metrics used to assess disease activity in RA (e.g., DAS28) are being applied to SLE (22–24). Indeed, studies have demonstrated that, in SLE, both joint tenderness and swelling can involve numerous joints in seeming contradiction to previous ideas that arthritis in SLE is characterized by tenderness out of proportion to swelling.

Along with a change in the findings noted on physical exam, new approaches to imaging have documented more objective findings of lupus arthritis (25–28). Ultrasound imaging of joints in SLE patients can demonstrate synovitis, with most studies concentrating on fingers and wrists. In addition, ultrasound can show prominent tenosynovitis, a finding that may be relevant to the development of deformity.

Even though SLE arthritis has been considered non-erosive (with the exception of the “rhupus” overlap), imaging by both ultrasound and magnetic resonance imaging (MRI) can show bone marrow changes. Changes of this kind are common in studies of RA and are thought to represent an early stage in the erosive process; nevertheless, it is possible that these changes indicate inflammation or edema in the bone marrow which may not progress to actual cortical breaks demonstrable by plain films.

The advances in imaging raise important questions concerning the best approach to assessing pain in arthritis in the clinical setting and developing a treatment strategy analogous to treat-to-target (T2T) in RA (29). Whereas in RA, the goal of treatment is to reduce pain and retard erosion and deformity, the goal in SLE is primarily to reduce pain since erosion seems uncommon or at least different in kind from that in RA. In view of recent studies showing that measures such as the DAS28 are applicable to RA, it appears reasonable to base treatment decisions on a tender and swollen joint count although symptoms and imaging may not be directly related. In SLE, the effects of certain cytokines may reduce levels of C-reactive protein, however, making it less reliable as a measure of inflammation (30).

Once a framework for assessing inflammatory arthritis in SLE is established in the routine care setting, then the usual agents to treat this condition include hydroxychloroquine, methotrexate, non-steroidal anti-inflammatory agents (NSAIDs), and glucocorticoids. Since a drug like belimumab is approved for non-renal manifestations of active, autoantibody positive SLE, it is often used for the treatment of arthritis since studies have indicated an effect on musculoskeletal manifestations as part of conventional measures of disease activity (31).

Myositis

While myalgia is not an uncommon source of pain in SLE, some patients develop signs and symptoms of an inflammatory myopathy (32, 33). In these patients, muscle pain and tenderness can accompany weakness. The frequency of myositis in SLE varies widely depending on the case definition and, for example, the requirement for elevation of creatinine phosphokinase (CPK) for diagnosis. One study suggested that myositis in SLE is marked by elevation of levels of aldolase rather than CPK (32). Evaluation for myositis would depend on findings of weakness although this assessment can be complicated by the presence of a steroid myopathy or deconditioning.

Avascular necrosis

In contrast to inflammatory arthritis, which is a sign of disease activity, avascular necrosis (AVN) is a sign of damage and a source of intense pain (34–36). This condition can affect multiple joints although large joints such as the knees and the hips are the most common. The etiology of AVN in SLE appears to be complex, with contributions from underlying immunological and hematologic disturbances as well as the effects of glucocorticoids. Whatever the exact interplay of these disturbances, AVN results from ischemia to bone with subsequent death and collapse.

Clotting disturbances, including the anti-phospholipid antibody syndrome (APS), are among potential factors contributing to the development of AVN in SLE but difficult to assess because of concurrent use of glucocorticoids.

Among its many actions that lead to damage in SLE, glucocorticoids are clearly associated with the development of AVN. Given the diverse manner that glucocorticoids are prescribed in SLE, determining the relationship of dose to the development of AVN is difficult. Thus, it is not clear whether the major determinant of AVN is total glucocorticoid dose, average glucocorticoid dose or highest glucocorticoid dose.

In general, the diagnosis of AVN is made by the basis of symptoms of pain, with plain films demonstrating various stages of radiographic progression. MRI is also a useful modality in evaluating pain in patients suspected of AVN; furthermore, it can show changes in regions that may not be symptomatic. As in the case of AVN in patients with other conditions, therapy includes surgery with core decompression and bone grafting as well as total joint replacement (TJR) (37). AVN is one of the most frequent reasons of TJR for patients and is one setting when more pain relief can be decisively achieved.

Fracture

Osteoporotic fracture is another source of musculoskeletal pain in SLE that appears complex in etiology (38–40). The most common locations are the hips, vertebrae and humerus. While glucocorticoid-induced osteoporosis (GIO) is a main etiology, other factors can lead to bone loss. These factors include vitamin D deficiency from sun avoidance, immobility, lack of weight-bearing exercise, lupus nephritis, disease duration, prior history of fracture and generalized disease activity. Bone loss is a feature of a pro-inflammatory state, with agents that can reduce inflammation potentially able to retard bone loss. Glucocorticoids, however, have their own direct effects on bone, leading to glucocorticoid-induced osteoporosis.

As in the case of AVN, the occurrence of fracture provides a strong impetus to limit glucocorticoid use by substitution of other agents without this complication. Prevention of GIO by anti-resorptive therapy can be an important strategy to reduce fracture risk. In SLE, however, the use of agents such as bis-phosphonates must take into account patient age and child-bearing potential since bis-phosphonates are pregnancy class C.

Osteoarthritis

With better therapy of SLE, the overall outcomes of patients with SLE have improved. Patients are living longer and, not surprisingly, osteoarthritis can occur, providing another source of pain in those patients with longstanding disease (41). While precise data on the frequency of osteoarthritis is difficult to obtain, the frequency of TJR in patients with SLE allows inference on the development of this condition (37). Unlike other musculoskeletal manifestations of SLE, osteoarthritis is difficult to categorize as either activity or damage.

Fibromyalgia

Of the various sources of musculoskeletal pain in SLE, fibromyalgia is among the most common (42, 43). Fibromyalgia is a chronic, painful condition in which disturbances in neuropsychologic function and sensitization lead to pain amplification (44–46). Widespread body pain is the hallmark, with tender points providing support for a role of pain amplification. Rather than calling fibromyalgia a disease or state, “fibromyalgianess” can be conceptualized as a trait which can also condition the perception of other painful conditions.

Despite causing significant distress, fibromyalgia does not fit well as either activity or damage; as such, fibromyalgia, along with other symptoms, may not receive the same efforts at treatment and prevention as those disease manifestations that are more clearly immunologically-mediated. As many studies show, fibromyalgia is frequent in SLE and, while the assessment of fibromyalgia can be difficult, the occurrence of this condition in SLE is far greater than the general population (42, 43). The coexistence of fibromyalgia and arthritis occurs with other inflammatory diseases such as spondyloarthritis, raising the possibility that it may be a consequence of localized pain, inflammation or stress (47).

In the context of other sources of musculoskeletal pain, awareness of fibromyalgia is important since it can allow interpretation of the findings of tenderness in the absence of swelling or high pain reports in patients with peripheral arthritis whose joint exam shows little or no evidence of synovitis.

NEUROPSYCHOLOGICAL SOURCES OF PAIN

Headache

Among sources of pain in SLE, headache is notable since it is a criterion for disease activity in the SLEDAI (18). Despite this standing, the nature of headache in SLE is unclear (48–51). Furthermore, it is unclear whether the frequency of headache in SLE is any greater than the general population, recognizing that the frequency of headache in the population depends on age and sex. One of the reasons for uncertainty about headache as a manifestation of SLE relates to the definition of headache by various organizations. For example, in the SLEDAI, lupus headache is defined as “severe persistent headache, may be migrainous, but must be nonresponsive to narcotic analgesia.” In contrast, the International Headache Society (IHS) provides a different categorization of headaches, in general, denoting tension headache as well as migraine headache with or without aura as common forms of headache in the population. Using the IHS criteria, most headaches in SLE can be readily characterized in the usual symptom categories. While such considerations do not exclude the existence of a distinct headache associated with disease activity, it seems reasonable to manage headache according to the usual approach for the general population.

Small fiber neuropathy

As a systemic disease, SLE has protean manifestations that occur with widely varying frequency. Although not included in the 19 neuropsychiatric syndromes as defined by the American College of Rheumatology (ACR) (52), small fiber neuropathy can lead to diffuse pain, burning, tingling, numbness, and changes in thermal sensation. Diagnosis is confirmed by skin biopsy demonstrating reduced intraepidermal nerve fiber density (53, 54). Treatment involves the usual medications for neuropathic pain; there are data supporting the use of intravenous IgG (55).

SEROSITIS

Pericarditis and pleuritis can both present with sudden and severe pain along with signs of inflammation and demonstration of effusions by either chest X-ray or ultrasound (56, 57). In contrast to other sources of pain that have been discussed, serositis represents an acute situation that demands prompt diagnosis and treatment, including exclusion of infection. Depending on the severity of these conditions, therapy may involve NSAIDs, colchicine or glucocorticoids.

For some patients with SLE, chest pain may occur in the absence of other evidence of pleuritis or pericarditis. These patients are often treated with anti-inflammatory agents even if the evidence for inflammation is scant. In this setting, there is concern about overtreatment with glucocorticoids.

Peritonitis can also present a diagnostic challenge since abdominal pain can signal a wide variety of serious visceral ailments, including emergent problems such as a perforation or bowel infarction. Therefore, diagnostic workup must be detailed, with concern for conditions that need surgical attention.

OTHER CONDITIONS

Patients with SLE can develop other sources of pain which may arise from immunological disturbances (e.g., vasculitis leading to infarction), effects of drugs (e.g., pancreatitis or esophagitis from glucocorticoids or NSAIDs) or coincidence. Not everything that occurs in patients with lupus need be attributed to that disease. For the more acute painful conditions, the workup has to be sufficient to exclude problems that would demand therapies other than anti-inflammatory or immunosuppressive agents.

SYMPTOM CATEGORIZATION

The Type 1-Type 2 Paradigm

According to current thinking about SLE pathogenesis, clinical manifestations can, in general, be divided into two broad categories: activity and damage (18, 58–60). This categorization suffices for manifestations such as nephritis where biopsies can show signs of inflammation (activity) or scarring and fibrosis (damage). Among the main complaints of patients with SLE are a series of symptoms that can be difficult to bin into these two categories. These symptoms include fatigue, pain, depression, sleep disturbance and perceived cognitive dysfunction. The origin of these symptoms is often obscure and seemingly lack a relationship to conventional measures of disease activity. It is perhaps surprising that one of the main complaints of patients (i.e., fatigue) does not signify disease activity; it also does not signify damage.

Our clinic has proposed a different scheme for symptom categorization in SLE that does not rely on the simple dichotomy of activity and damage. Rather, we have proposed that symptoms of SLE activity can be divided into two main categories or bins which are simply called Type 1 and Type 2 symptoms. As noted before, Type 1 symptoms are the classical signs and symptoms of SLE that can be clearly ascribed to inflammation and autoreactivity. Nephritis is at the top of the list. There are excellent biomarkers for nephritis in terms of renal function, tissue pathology and serology. Rash is another example of Type 1 manifestation where immune mechanism can be established. Importantly, some Type 1 manifestations are asymptomatic and patients may be unaware of serious renal disease.

In contrast to Type 1 manifestations, Type 2 manifestations are all symptomatic, with the magnitude, persistence and pervasiveness of these symptoms often dominating patient experience of illness. For Type 2 symptoms, it can be difficult to establish a link between the symptoms, on the one hand, and inflammation and autoreactivity, on the other hand. Furthermore, by their nature, some of these symptoms can be multifactorial in origin. For example, depression can result from the burden of chronic illness, unrelenting pain, and loss of employment and disability.

While Type 2 symptoms may not show obvious links to inflammation, they may, nevertheless, result from immune activity. Thus, cytokines can act as mediators in the central and peripheral nervous system and there is substantial evidence that pro-inflammatory cytokines contribute to symptoms of pain, fatigue and depression. Clinical trials have shown efficacy of TNF-α blockers in ordinary depression although the benefits may be greatest in those with elevation of CRP (61). Similarly, TNF-α blockers have reduced depression in patients with psoriasis (62).

As a group, pain, fatigue, depression and cognitive dysfunction often track together especially in patients with chronic inflammatory disease. In this setting, the array of symptoms is analogous to so-called “sickness behavior” that describes the symptoms that accompany acute inflammatory and infectious illnesses (63). These symptoms are part of an overall host response which can influence energy metabolism to shift nutrients to fuel an immune response to overcome infection. The infected (or inflamed) person becomes tired and sedentary, showing weakness, lassitude and pain to defer more strenuous activities that would be energetically demanding. While this program may have evolved for acute host defense and be physiologic or protective in the acute setting, it can be replayed in the setting of a chronic inflammatory disease and become pathologic (64, 65).

The division of symptoms into Type 1 and Type 2 categories does not mean that Type 2 symptoms are totally or substantially independent of inflammatory mediators. Rather, the division signifies that the two types of symptoms can occur independently, with Type 2 symptoms often dissociated from flares of SLE and increases in measures of disease. Importantly, the division indicates that therapies necessary to reduce Type 1 and Type 2 symptoms may be different and that immunosuppressive Type 1 symptoms may not attenuate Type 2 symptoms. As manifestations of SLE, Type 2 symptoms demand their own therapies as part of a more comprehensive treatment program even if these therapies are seemingly unrelated to the immune system. On the other hand, data from clinical trials indicate an effect of belimumab on fatigue (66). Importantly, patients can have both Type 1 and Type 2 manifestations in varying extents (Figure 1).

graphic file with name nihms-1896986-f0001.jpg

Open in a new tab

The figure illustrates the relationship between Type 1 and Type 2 manifestations, demonstrating the overlap between the two categories. Some patients may report neither Type 1 nor Type 2 symptoms and can be considered to have minimal SLE.

The rationale of the Type 1-Type 2 system for the management of pain

The Type 1-Type 2 categorization is a theoretic construct whose goal is to elucidate better the origin of symptoms, including pain, in patients with SLE; to enhance patient-provider communication; and to improve patient quality-of-life by addressing the full gamut of patient symptoms. In this construct, the totality of symptoms that the patient reports constitute their “lupus” since that is how patients understand their disease. Unlike investigators or practitioners, patients do not engage in attribution since they want relief from the full range of symptoms.

As shown by many studies, there is frequent discordance between patients and providers in the assessment of disease activity or severity, contributing to problems in communication and patient dissatisfaction (10–12). We believe that this discordance relates in part to the relative weight that patients and providers place on different disease manifestations. While providers may focus on Type 1 manifestations to form an assessment of disease activity, patients may focus on Type 2 manifestations since these manifestations, by their nature, are very symptomatic. In terms of pain, the provider may perform a joint exam and find minimal tenderness, concluding that arthritis is inactive. In contrast, the patient may be experiencing widespread pain, with fibromyalgia underlying the patient assessment that the disease is very active.

Regarding that both Type 1 and Type 2 symptoms are essential elements in disease has important implications for therapy. First, patient-provider communication can be enhanced by validating the symptoms that patients report (e.g., fibromyalgia) are, indeed, part of their condition, requiring evaluation and treatment. Second, by recognizing that Type 1 and Type 2 symptoms may have distinct origins even in the same patient, the provider can choose therapy more appropriately, expanding beyond the base of immunosuppressive agents. A more thoughtful approach to therapy based on the Type 1-Type 2 categorization can limit the use of corticosteroids for problems that are not primarily inflammatory in origin.

Just as categorization of symptoms into Type 1 and Type 2 bins may reduce the use of immunosuppressive agents, it may also increase the use of other classes of drugs related to fibromyalgia or depression. As a study from our clinic has found, depression in SLE is frequently undertreated since it is not clearly a manifestation of neuropsychologic lupus and can be complex in etiology (67). By incorporating depression in the Type 1-Type 2 paradigm, the issue of attribution becomes less pressing and a more satisfactory treatment plan can be developed to include exercise and stress reduction, for example.

The application of the Type 1-Type 2 paradigm to treatment

In our clinic, we have begun more formal application of the Type 1-Type 2 system in routine care and are constructing a research platform to investigate many issues that flow from this type of a more holistic patient approach.

At present, there a variety of measures for Type 1 disease that range from patient reports and surveys for disease activity to laboratory testing to sophisticated molecular analyses to interrogate immune response. The measures for Type 2 disease are also many but, in general, there are patient reports that have been developed for other settings (e.g., depression, fatigue) not necessarily related to lupus. The use of measures for Type 2 manifestation at this time must be borrowed from other conditions pending the development of measures that are more specific for SLE.

For our initial operationalization of care according to the Type 1-Type 2 system, we have used the SLEDAI for Type 1 disease activity. For Type 2, we have used the 2011 ACR fibromyalgia criteria, considering: (1) a widespread index score ≥7 and symptom severity score ≥5 or, (2) widespread pain index ≥3 and symptom severity score ≥9 as indicative of Type 2 disease. We chose this measure since it does relate to pain, a major Type 2 symptom, and is consistent with studies indicating the frequency of fibromyalgia in SLE (42, 43). In using this scale, we are considering fibromyalgia as a trait that can be of varying intensity or severity. In our use, the total fibromyalgia severity score (sum of widespread pain index and symptom severity score) can provide a measure of “fibromyalgianess” which can lead to symptoms itself (i.e., widespread body pain) or color or condition the reporting of other symptoms (e.g., hair loss, chest pain).

Our first study showed how the incorporation of assessment for both Type 1 and Type 2 can lead to a new and hopefully more informative categorization of patients that goes beyond the more classic activity-damage dichotomy (14). The use of two measures allows the delineation of four patient groups as indicated in Table 3 although more subdivisions are possible.

TABLE 3.

Categorization of Symptoms in SLE *

Type 1 SLE: active SLE without meeting fibromyalgia or PSD criteria
Type 2 SLE: inactive SLE meeting fibromyalgia or PSD criteria
Mixed SLE: active SLE meeting fibromyalgia or PSD criteria
Minimal SLE: inactive SLE without meeting fibromyalgia or PSD criteria.
Open in a new tab
*

In our studies, we have identified Type 2 SLE using either criteria for fibromyalgia or polysymptomatic distress (PSD).

Using the Type 1 and Type 2 categorization, we found that 20% of patients can be categorized as having high Type 2 SLE activity. As a group, patients with Type 2 SLE activity had more severe self-reported lupus activity and higher rates of lupus flares than those without Type 2 activity. Moreover, we found that patients with Type 2 SLE reported higher frequency of many symptoms including fatigue, muscle pain, forgetfulness and headache; they also reported symptoms that are potentially inflammatory in origin. Although synovitis was not documented on exam in Type 2 SLE patients, the frequency of self-reported joint swelling was similar between patients with Type 1 and Type 2 SLE.

Our understanding and application of the Type 1 and Type 2 SLE model is in evolution, with, for example, a preliminary cluster analysis indicating there may be more than four categories of Type 1 and Type 2 SLE symptoms including those with fatigue predominant Type 2. Moreover, we have found that the severity of Type 1 and Type 2 activity can fluctuate between visits even resulting in a change in category (68).

CONCLUSION

Pain in SLE is a major symptom of patients and can result from a wide variety of processes. While some types of pain may result from immunological mechanisms associated with inflammation and autoreactivity, other types of pain appear to reflect central mechanisms. To understand and treat pain more effectively, we have proposed a new system to divide symptoms of lupus into two broad categories, both of which are intrinsic features of disease. Hopefully, this categorization will promote better communication between patients and providers and represent a more effective framework for treating one of the most persistent, severe and disabling manifestations of SLE.

Key points:

Lupus is a systemic autoimmune disease characterized by multiple sources of pain.

Arthritis is the most common form of musculoskeletal pain in lupus.

Symptoms in lupus can be divided into two categories called Type 1 and Type 2.

Type 1 and Type 2 symptoms can differ in response to immunosuppressive agents.

Fibromyalgia can cause widespread pain in lupus.

Synopsis.

Systemic lupus erythematous is a systemic autoimmune disease that can cause severe pain and impair quality of life. Pain in lupus can arise from a variety of mechanisms and is usually assessed in terms of activity and damage. In contrast, categorization of symptoms as Type 1 and Type 2 manifestations encompasses a broader array of symptoms including widespread pain, fatigue and depression that may track together. The categorization of symptoms as Type 1 and Type 2 manifestations can facilitate communication between patient and provider and provide a framework to address more fully the complex symptoms experienced by patients.

CLINICS CARE POINTS.

The approach to therapy of patients with SLE can be based on division of the manifestations into two categories.

Inflammatory manifestations (Type 1) are related to disease activity and include arthritis and nephritis. These manifestations can respond to immunomodulatory agents.

Non-inflammatory manifestations (Type 2) include widespread pain, fatigue, depression and sleep disturbance. These manifestations do not generally respond to immunomodulatory agents and need other treatments.

Type 2 manifestations represent some of the common and persistent symptoms of SLE and can impact quality of life.

Type 1 manifestations can be assessed by the SLEDAI while Type 2 manifestations can be assessed by instruments for fibromyalgia and fatigue.

Acknowledgement:

Amanda M. Eudy acknowledges the grant support of NIH NCATS 1KL2TR002554

Footnotes

Disclosure: The authors have no conflicts of interest to disclose.

REFERENCES

  • 1.Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet. 2014;384:1878–88. [DOI] [PubMed] [Google Scholar]
  • 2.Kaul A, Gordon C, Crow MK, Touma Z, Urowitz MB, van Vollenhoven R, et al. Systemic lupus erythematosus. Nature reviews Disease primers. 2016;2:16039. [DOI] [PubMed] [Google Scholar]
  • 3.Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365:2110–21. [DOI] [PubMed] [Google Scholar]
  • 4.Catalina MD, Owen KA, Labonte AC, Grammer AC, Lipsky PE. The pathogenesis of systemic lupus erythematosus: Harnessing big data to understand the molecular basis of lupus. J Autoimmun. 2020;110:102359. [DOI] [PubMed] [Google Scholar]
  • 5.Waldheim E, Elkan AC, Bergman S, Frostegård J, van Vollenhoven R, Henriksson EW. Extent and characteristics of self-reported pain in patients with systemic lupus erythematosus. Lupus. 2013;22:136–43. [DOI] [PubMed] [Google Scholar]
  • 6.Yazdany J, Yelin E. Health-related quality of life and employment among persons with systemic lupus erythematosus. Rheum Dis Clin North Am. 2010;36:15–32, vii. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Waldheim E, Elkan AC, Pettersson S, van Vollenhoven R, Bergman S, Frostegård J, et al. Health-related quality of life, fatigue and mood in patients with SLE and high levels of pain compared to controls and patients with low levels of pain. Lupus. 2013;22:1118–27. [DOI] [PubMed] [Google Scholar]
  • 8.Fonseca R, Bernardes M, Terroso G, de Sousa M, Figueiredo-Braga M. Silent burdens in disease: fatigue and depression in SLE. Autoimmune diseases. 2014;2014:790724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Azizoddin DR, Gandhi N, Weinberg S, Sengupta M, Nicassio PM, Jolly M. Fatigue in systemic lupus: the role of disease activity and its correlates. Lupus. 2019;28:163–73. [DOI] [PubMed] [Google Scholar]
  • 10.Alarcon GS, McGwin G Jr., Brooks K, Roseman JM, Fessler BJ, Sanchez ML, et al. Systemic lupus erythematosus in three ethnic groups. XI. Sources of discrepancy in perception of disease activity: a comparison of physician and patient visual analog scale scores. Arthritis Rheum. 2002;47:408–13. [DOI] [PubMed] [Google Scholar]
  • 11.Neville C, Clarke AE, Joseph L, Belisle P, Ferland D, Fortin PR. Learning from discordance in patient and physician global assessments of systemic lupus erythematosus disease activity. J Rheumatol. 2000;27:675–9. [PubMed] [Google Scholar]
  • 12.Golder V, Ooi JJY, Antony AS, Ko T, Morton S, Kandane-Rathnayake R, et al. Discordance of patient and physician health status concerns in systemic lupus erythematosus. Lupus. 2018;27(3):501–6. [DOI] [PubMed] [Google Scholar]
  • 13.Pisetsky DS, Clowse MEB, Criscione-Schreiber LG, Rogers JL. A novel system to categorize the symptoms of systemic lupus erythematosus. Arthritis Care Res. 2019;71:735–41. [DOI] [PubMed] [Google Scholar]
  • 14.Rogers JL, Eudy AM, Pisetsky D, Criscione-Schreiber LG, Sun K, Doss J, et al. Utilizing clinical characteristics and patient-reported outcome measures to categorize lupus subtypes. Arthritis Care Res. 2020;online: ahead of print. [DOI] [PubMed] [Google Scholar]
  • 15.Dall’Era M, Wofsy D. Clinical trial design in systemic lupus erythematosus. Curr Opin Rheumatol. 2006;18:476–80. [DOI] [PubMed] [Google Scholar]
  • 16.Grossman JM. Lupus arthritis. Best practice & research Clinical rheumatology. 2009;23:495–506. [DOI] [PubMed] [Google Scholar]
  • 17.Ceccarelli F, Perricone C, Cipriano E, Massaro L, Natalucci F, Capalbo G, et al. Joint involvement in systemic lupus erythematosus: from pathogenesis to clinical assessment. Semin Arthritis Rheum. 2017;47:53–64. [DOI] [PubMed] [Google Scholar]
  • 18.Bombardier C, Gladman DD, Urowitz MB, Caron D, Chang CH. Derivation of the SLEDAI. A disease activity index for lupus patients. The Committee on Prognosis Studies in SLE. Arthritis Rheum. 1992;35:630–40. [DOI] [PubMed] [Google Scholar]
  • 19.Petri M, Orbai AM, Alarcon GS, Gordon C, Merrill JT, Fortin PR, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64:2677–86. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Aringer M, Costenbader K, Daikh D, Brinks R, Mosca M, Ramsey-Goldman R, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis Rheumatol. 2019;71:1400–12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Aletaha D, Smolen JS. Diagnosis and management of rheumatoid arthritis: a review. JAMA. 2018;320:1360–72. [DOI] [PubMed] [Google Scholar]
  • 22.Castrejón I, Yazici Y, Pincus T. Patient self-report RADAI (Rheumatoid Arthritis Disease Activity Index) joint counts on an MDHAQ (Multidimensional Health Assessment Questionnaire) in usual care of consecutive patients with rheumatic diseases other than rheumatoid arthritis. Arthritis Care Res. 2013;65:288–93. [DOI] [PubMed] [Google Scholar]
  • 23.Ceccarelli F, Perricone C, Massaro L, Pacucci VA, Cipriano E, Truglia S, et al. The role of disease activity score 28 in the evaluation of articular involvement in systemic lupus erythematosus. TheScientificWorldJournal. 2014;2014:236842. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Cipriano E, Ceccarelli F, Massaro L, Spinelli FR, Alessandri C, Perricone C, et al. Joint involvement in patients affected by systemic lupus erythematosus: application of the swollen to tender joint count ratio. Reumatismo. 2015;67:62–7. [DOI] [PubMed] [Google Scholar]
  • 25.Tani C, D’Aniello D, Possemato N, Delle Sedie A, Caramella D, Bombardieri S, et al. MRI pattern of arthritis in systemic lupus erythematosus: a comparative study with rheumatoid arthritis and healthy subjects. Skeletal Radiol. 2015;44:261–6. [DOI] [PubMed] [Google Scholar]
  • 26.Piga M, Saba L, Gabba A, Congia M, Balestrieri A, Mathieu A, et al. Ultrasonographic assessment of bone erosions in the different subtypes of systemic lupus erythematosus arthritis: comparison with computed tomography. Arthritis research & therapy. 2016;18:222. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Torrente-Segarra V, Monte TCS, Corominas H. Musculoskeletal involvement and ultrasonography update in systemic lupus erythematosus: new insights and review. European journal of rheumatology. 2018;5:127–30. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zollars ES, Hyer M, Wolf B, Chapin R. Measuring lupus arthritis activity using contrasted high-field MRI. Associations with clinical measures of disease activity and novel patterns of disease. Lupus science & medicine. 2018;5:e000264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75:3–15. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Enocsson H, Sjowall C, Skogh T, Eloranta ML, Ronnblom L, Wettero J. Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares? Arthritis Rheum. 2009;60:3755–60. [DOI] [PubMed] [Google Scholar]
  • 31.Manzi S, Sánchez-Guerrero J, Merrill JT, Furie R, Gladman D, Navarra SV, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012;71:1833–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Tsokos GC, Moutsopoulos HM, Steinberg AD. Muscle involvement in systemic lupus erythematosus. JAMA. 1981;246:766–8. [PubMed] [Google Scholar]
  • 33.Liang Y, Leng RX, Pan HF, Ye DQ. Associated variables of myositis in systemic lupus erythematosus: a cross-sectional study. Med Sci Monit. 2017;23:2543–9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Tse SM, Mok CC. Time trend and risk factors of avascular bone necrosis in patients with systemic lupus erythematosus. Lupus. 2017;26:715–22. [DOI] [PubMed] [Google Scholar]
  • 35.Gladman DD, Dhillon N, Su J, Urowitz MB. Osteonecrosis in SLE: prevalence, patterns, outcomes and predictors. Lupus. 2018;27:76–81. [DOI] [PubMed] [Google Scholar]
  • 36.Kwon HH, Bang SY, Won S, Park Y, Yi JH, Joo YB, et al. Synergistic effect of cumulative corticosteroid dose and immunosuppressants on avascular necrosis in patients with systemic lupus erythematosus. Lupus. 2018;27:1644–51. [DOI] [PubMed] [Google Scholar]
  • 37.Kasturi S, Goodman S. Current perspectives on arthroplasty in systemic lupus erythematosus: rates, outcomes, and adverse events. Curr Rheumatol Rep. 2016;18:59. [DOI] [PubMed] [Google Scholar]
  • 38.Bultink IE, Harvey NC, Lalmohamed A, Cooper C, Lems WF, van Staa TP, et al. Elevated risk of clinical fractures and associated risk factors in patients with systemic lupus erythematosus versus matched controls: a population-based study in the United Kingdom. Osteoporos Int. 2014;25:1275–83. [DOI] [PubMed] [Google Scholar]
  • 39.Carli L, Tani C, Spera V, Vagelli R, Vagnani S, Mazzantini M, et al. Risk factors for osteoporosis and fragility fractures in patients with systemic lupus erythematosus. Lupus science & medicine. 2016;3:e000098. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Tedeschi SK, Kim SC, Guan H, Grossman JM, Costenbader KH. Comparative fracture risks among United States Medicaid enrollees with and those without systemic lupus erythematosus. Arthritis Rheumatol. 2019;71:1141–6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.Aksoy A, Solmaz D, Can G, Cetin P, Balci A, Akar S, et al. Increased frequency of hand osteoarthritis in patients with primary Sjögren syndrome compared with systemic lupus erythematosus. J Rheumatol. 2016;43:1068–71. [DOI] [PubMed] [Google Scholar]
  • 42.Huang FF, Fang R, Nguyen MH, Bryant K, Gibson KA, O’Neill SG. Identifying co-morbid fibromyalgia in patients with systemic lupus erythematosus using the Multi-Dimensional Health Assessment Questionnaire. Lupus. 2020;29:1404–11. [DOI] [PubMed] [Google Scholar]
  • 43.Wolfe F, Petri M, Alarcon GS, Goldman J, Chakravarty EF, Katz RS, et al. Fibromyalgia, systemic lupus erythematosus (SLE), and evaluation of SLE activity. J Rheumatol. 2009;36:82–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Clauw DJ. Fibromyalgia: a clinical review. JAMA. 2014;311:1547–55. [DOI] [PubMed] [Google Scholar]
  • 45.Wolfe F, Clauw DJ, Fitzcharles MA, Goldenberg DL, Häuser W, Katz RL, et al. 2016 revisions to the 2010/2011 fibromyalgia diagnostic criteria. Semin Arthritis Rheum. 2016;46:319–29. [DOI] [PubMed] [Google Scholar]
  • 46.Wolfe F, Walitt BT, Rasker JJ, Katz RS, Häuser W. The polysymptomatic distress scale is simple, useful, and effective in clinical care and clinical and epidemiology studies. J Rheumatol. 2016;43:454. [DOI] [PubMed] [Google Scholar]
  • 47.Alunno A, Carubbi F, Stones S, Gerli R, Giacomelli R, Baraliakos X. The impact of fibromyalgia in spondyloarthritis: from classification criteria to outcome measures. Front Med. 2018;5:290. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 48.Cuadrado MJ, Sanna G. Headache and systemic lupus erythematosus. Lupus. 2003;12:943–6. [DOI] [PubMed] [Google Scholar]
  • 49.Mitsikostas DD, Sfikakis PP, Goadsby PJ. A meta-analysis for headache in systemic lupus erythematosus: the evidence and the myth. Brain. 2004;127:1200–9. [DOI] [PubMed] [Google Scholar]
  • 50.Lessa B, Santana A, Lima I, Almeida JM, Santiago M. Prevalence and classification of headache in patients with systemic lupus erythematosus. Clin Rheumatol. 2006;25:850–3. [DOI] [PubMed] [Google Scholar]
  • 51.Davey R, Bamford J, Emery P. The ACR classification criteria for headache disorders in SLE fail to classify certain prevalent headache types. Cephalalgia. 2008;28:296–9. [DOI] [PubMed] [Google Scholar]
  • 52.The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599–608. [DOI] [PubMed] [Google Scholar]
  • 53.Gøransson LG, Tjensvoll AB, Herigstad A, Mellgren SI, Omdal R. Small-diameter nerve fiber neuropathy in systemic lupus erythematosus. Arch Neurol. 2006;63:401–4. [DOI] [PubMed] [Google Scholar]
  • 54.Bortoluzzi A, Silvagni E, Furini F, Piga M, Govoni M. Peripheral nervous system involvement in systemic lupus erythematosus: a review of the evidence. Clin Exp Rheumatol. 2019;37:146–55. [PubMed] [Google Scholar]
  • 55.Liu X, Treister R, Lang M, Oaklander AL. IVIg for apparently autoimmune small-fiber polyneuropathy: first analysis of efficacy and safety. Ther Adv Neurol Disord. 2018;11:1756285617744484. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Man BL, Mok CC. Serositis related to systemic lupus erythematosus: prevalence and outcome. Lupus. 2005;14:822–6. [DOI] [PubMed] [Google Scholar]
  • 57.Dein E, Douglas H, Petri M, Law G, Timlin H. Pericarditis in lupus. Cureus. 2019;11:e4166. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Gladman D, Ginzler E, Goldsmith C, Fortin P, Liang M, Urowitz M, et al. The development and initial validation of the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index for systemic lupus erythematosus. Arthritis Rheum. 1996;39:363–9. [DOI] [PubMed] [Google Scholar]
  • 59.Griffiths B, Mosca M, Gordon C. Assessment of patients with systemic lupus erythematosus and the use of lupus disease activity indices. Best practice & research Clinical rheumatology. 2005;19:685–708. [DOI] [PubMed] [Google Scholar]
  • 60.Lam GK, Petri M. Assessment of systemic lupus erythematosus. Clin Exp Rheumatol. 2005;23:S120–32. [PubMed] [Google Scholar]
  • 61.Raison CL, Rutherford RE, Woolwine BJ, Shuo C, Schettler P, Drake DF, et al. A randomized controlled trial of the tumor necrosis factor antagonist infliximab for treatment-resistant depression: the role of baseline inflammatory biomarkers. JAMA psychiatry. 2013;70:31–41. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 62.Fleming P, Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, et al. Effect of biologics on depressive symptoms in patients with psoriasis: a systematic review. J Eur Acad Dermatol Venereol. 2015;29:1063–70. [DOI] [PubMed] [Google Scholar]
  • 63.Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am. 2009;29:247–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Straub RH, Schradin C. Chronic inflammatory systemic diseases: an evolutionary trade-off between acutely beneficial but chronically harmful programs. Evolution, medicine, and public health. 2016;2016:37–51. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Straub RH. The brain and immune system prompt energy shortage in chronic inflammation and ageing. Nat Rev Rheumatol. 2017;13:743–51. [DOI] [PubMed] [Google Scholar]
  • 66.Strand V, Berry P, Lin X, Asukai Y, Punwaney R, Ramachandran S. Long-term impact of Belimumab on health-related quality of life and fatigue in patients with systemic lupus erythematosus: six years of treatment. Arthritis Care Res. 2019;71:829–38. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.Karol DE, Criscione-Schreiber LG, Lin M, Clowse ME. Depressive symptoms and associated factors in systemic lupus erythematosus. Psychosomatics. 2013;54:443–50. [DOI] [PubMed] [Google Scholar]
  • 68.Eudy AM, Rogers JL, Whitney R, Criscione-Schreiber L, Doss J, Pisetsky DS, et al. Longitudinal changes in manifestations of SLE (abstract). Arthritis Rheumatol. 2019;71(Suppl 10). [Google Scholar]

RESOURCES