Rheumatologic diseases

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

FA Manian MD, MPH, , , , , , , , , , , , , , , 1 Comment

Although the connection between Covid-19 vaccination and gout flare has yet to be established, higher rates of gout/gout flare following the administration of several other vaccines (eg, influenza, tetatnus, recombinant zoster) have been reported.1  Thus, it is conceivable that Covid-19 vaccine may also be associated with gout flare as more and more people are immunized.  

A 2019 prospective study of over 500 patients with gout found that vaccination was associated with 2-fold higher odds of gout flare (aO.R. 1.99; 95% ci 1.01-3.89) during the 2 day period following immunization; no information on the type of vaccines administered was provided, however.1  Similarly,  higher risk of gout (3.6-fold) has been reported in recipients of recombinant zoster vaccine following immunization.1

An intriguing mechanism explaining the association of vaccination and gout flare is the activation of the Nlrp3 inflammasome, a multiprotein complex produced in response to diverse stimuli such as uric acid crystals and ATP released from tissue injury/necrotic cells.2 Of interest, ~25% of patients with asymptomatic hyperuricemia have been found to have evidence of monosodium urate crystals in and around their joints by advanced imaging, such that vaccination may potentially bring out more inflammatory response and gout flare. 3 

Although aluminum adjuvants intended to increase the immunogenicity of one-half of all routine adult vaccines (eg, tetanus, diphteria, pertussis) have been shown to activate the Nlrp3 inflammasome in vitro, neither currently available mRNA vaccines (Pfizer, Moderna) nor the Johnson&Johnson vaccine contains aluminum as an adjuvant. 4  

Despite the potential for gout flare following adult vaccination, it should be emphasized that the absolute risk is still low and pales compared to the overwhelming benefits of vaccination in general.1

Bonus Pearl: Did you know that, in addition to the usual uric acid lowering drugs, losartan, fenofibrate and some non-steroidal anti-inflammatory drugs, such as indomethacin, also lower serum uric acid levels? 5,6

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References

  1. Yokose C, McCormick N, Chen C, et al. Risk of gout flares after vaccination: a prospective case-crossoverstudy. Ann Rheum Dis 2019;78:1601-1604. https://ard.bmj.com/content/early/2019/07/31/annrheumdis-2019-215724.info?versioned=true
  2. Lyer SS, Pulskens WP, Sadler JJ, et al. Necrotic cells trigger a sterile inflammatory response throught the Nlrp3 inflammasome. PNAS 2009;106:20388-20393. https://pubmed.ncbi.nlm.nih.gov/19918053/
  3. Yokose C, Choi H. Response to “Clarification regarding the statement of the association between the recombinant zoster vaccine (RZV) and gout flares’ by Didierlaurent etal. Ann Rheum Dis Month, December 2019. https://ard.bmj.com/content/annrheumdis/early/2019/12/18/annrheumdis-2019-216670.full.pdf
  4. Covid-19 vaccine information. https://covidvaccine.mo.gov/ Accessed March 16, 2021.
  5. Daskalopoulou SS, Tzovaras V, Mikhailidis DP, et al. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Current Pharmaceutical Design 2005;11:4161-75. https://www.eurekaselect.com/60510/article
  6. Tiitinen S, Nissila M, Ruutsalo HM, et al. Effect of nonsteroidal anti-inflammatory drugs on the renal excretion of uric acid. Clin Rheumatol 1983;2:233-6. https://pubmed.ncbi.nlm.nih.gov/6678696/#:~:text=The%20effect%20of%209%20nonsteroidal,studied%20had%20no%20significant%20influence.

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

My elderly patient developed a flare-up of her gout few days after receiving Covid-19 vaccine. Is there a connection between immunization and gout flare?

Is my patient with gout at higher risk of cancer?

FA Manian MD, MPH, , , , , , , , , , , , , , , , Leave a comment

Although the association of gout with cardiovascular disease, chronic kidney disease, hypertension, diabetes mellitus or obesity is well known, increasingly number of epidemiologic studies support the association of gout with higher risk of malignancy. 1,2

A 2015 meta-analysis of 3 studies involving over 50,000 persons concluded that gout was an independent risk factor for cancer, particularly urological, gastrointestinal and lung cancers. 1

A population-based study of comorbidities in over 2 million persons in Sweden found that in addition to an increased risk of diabetes mellitus, hypertension, chronic heart failure, chronic kidney disease and alcohol abuse, gout was associated with increased risk of malignancy: odds ratio 1.3 (1.2-1.5) in men and 1.1 (1.1-1.2) in women. 2

Although serum uric acid has been considered to have anti-oxidant properties, a prospective study of over 28,000 women followed over a median of 15.2 years did not find high serum acid levels to be protective of cancer.3 In fact, uric acid levels > 5.4 mg/dL at the time of subject enrollment was independently associated with increased risk of total cancer mortality and deaths from a variety of malignant neoplasms, including those of breast, female genital organs, and nervous systems. 3 In a similar prospective study involving men, high uric acid levels (>6.7 mg/dL) were associated with increased risk of mortality from gastrointestinal, respiratory and intrathoracic organ malignancies. 4

Whether the observed association between gout and higher risk of malignancy is causal or due to the company that gout often keeps (eg, lifestyle) is unclear.

Fun fact: Did you know that among mammals, only humans, great apes and certain breeds of dogs (eg, Dalmation) produce elevated levels of uric acid in the urine and blood? 5

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References

  1. Wang W, Xu D, Wang B, et al. Increased risk of cancer in relation to gout: a review of three prospective cohort studies with 50,358 subjects. Mediators of Inflammation 2015, Article ID 680853, 6 pages. https://www.ncbi.nlm.nih.gov/pubmed/26504360
  2. Wandell P. Gout and its comorbidities in the total population of Stockholm. Preventive Medicine 2015; 81:387-91. ISSN 0091-7435. https://www.ncbi.nlm.nih.gov/pubmed/26500085
  3. Strasak AM, Rapp K, Hilbe W, et al. The role of serum uric acid as an antioxidant protecting against cancer: prospective study in more than 28000 older Austrian women. Ann Onc 2007;18:1893-97. https://www.ncbi.nlm.nih.gov/pubmed/17785768
  4. Strasak Am, Hilbe RK, Oberaingner W, et al. Serum uric acid and risk of cancer mortality in a large prospective male cohort. Cancer Causes Control 2007;18:1021-9. https://www.ncbi.nlm.nih.gov/pubmed/17665312
  5. Bannasch D, Safra N, Young A, et al. Mutations in the SLC2A9 gene cause hyperuriosuria and hyperuricemia in the dog. PLOS Genet 2008;4:e1000246. https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1000246&type=printable
Is my patient with gout at higher risk of cancer?

When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

FA Manian MD, MPH, , , , , Leave a comment

Think of invasive pulmonary aspergillosis (IPA) in your patient when she or he has a COPD exacerbation that appears refractory to broad-spectrum antibiotics and high doses of steroids. Heighten your suspicion even more in patients with severe-steroid dependent COPD, presence of a new pulmonary infiltrate or isolation of Aspergillus spp from respiratory cultures. 1

It’s worth remembering that although dyspnea and bronchospasm are found in most COPD patients with IPA, in contrast to haematological patients, fever, chest pain and hemoptysis are usually absent in this patient population.1

Diagnosis of IPA in this patient population is challenging for several reasons including: 1. A definitive or “proven” diagnosis requires histopathologic evidence of Aspergillus invasion of lung tissue which is not possible without subjecting an already fragile patient to invasive procedures (eg, lung aspiration or biopsy); 2. In contrast to IPA in highly susceptible immunocompromised patients with cancer and recipients of hematopoietic stem cell transplants, standardized definition of IPA in patients with COPD is lacking; 1,3 and 3. Frequent colonization of the respiratory tract of COPD patients with Aspergillus spp (16.3 per 1000 COPD admission in 1 study) 4,5, makes it difficult to diagnose IPA based on cultures alone.

Aside from respiratory cultures, another non-invasive test, serum galactomannan (GM, a polysaccharide antigen that exists primarily in the cell walls of Aspergillus spp and released into the blood during its growth phase 6) may have some utility in suggesting IPA in COPD patients, albeit with a mediocre sensitivity (~30-60%) but respectable specificity (>80 %). In contrast, bronchoalveolar lavage fluid GM may have better sensitivity  (~75%-90%) with similar specificity as that of serum GM in the diagnosis of IPA in these patients 7-8

Bonus pearl: Did you know that the incidence of IPA appears to be increasing in COPD patients requiring ICU admission, with reported mortality rates of 67% to 100%? 7

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References

  1. Bulpa P, Dive A, Sibille Y. Invasive pulmonary aspergillosis in patients with chronic obstructive pulmonary disease. Eur Res J 2007;30:782-800. https://www.ncbi.nlm.nih.gov/pubmed/17906086
  2. Bulpa P, Bihin B, Dimopoulos G, et al. Which algorithm diagnoses invasive pulmonary aspergillosis best in ICU patietns with COPD? Eur Resir J 2017;50:1700532 https://www.ncbi.nlm.nih.gov/pubmed/28954783
  3. Barberan J, Garcia-Perez FJ, Villena V, et al. Development of aspergillosis in a cohort of non-neutropenic, non-transplant patients colonized by Aspergillus spp. BMC Infect Dis 2017;17:34. https://link.springer.com/article/10.1186/s12879-016-2143-5
  4. Guinea J, Torres-Narbona M, Gijon P, et al. Pulmonary aspergillosis in patients with chronic obstructive pulmonary disease: incidence, risk factors, and outcome. Clin Microbiol Infect 2010; 16:870-77. https://www.sciencedirect.com/science/article/pii/S1198743X14617432
  5. Blot Stijn I, Taccone FS, Van den Abeele A-M, et al. A clinical algorithm to diagnose invasive pulmonary aspergillosis in critically ill patients. Am J Respir Crit Care Med 202;186:56-64. https://www.atsjournals.org/doi/full/10.1164/rccm.201111-1978OC
  6. Pfeiffer CD, Fine JP, Safdar N. Diagnosis of invasive aspergillosis using a galactomannan assay: a meta-analysis. Clin Infect Dis 2006;42:1417-27. https://academic.oup.com/cid/article/42/10/1417/278148
  7. He H, Ding L, Sun B, et al. Role of galactomannan determinations in bronchoalveolar lavage fluid samples from critically ill patients with chronic obstructive pulmonary disease for the diagnosis of invasive pulmonary aspergillosis: a prospective study. Critical Care 2012;16:R138. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5066034/
  8. Zhou W, Li H, Zhang Y, et al. Diagnostic value of galactomannan antigen test in serum and bronchoalveolar lavage fluid samples from patients with nonneutropenic invasive pulmonary aspergillosis. J Clin Microbiol 2017;55:2153-61. https://www.ncbi.nlm.nih.gov/pubmed/28446576
When should I suspect invasive pulmonary aspergillosis in my patient with COPD exacerbation?

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

FA Manian MD, MPH, , , , , Leave a comment

It is generally recommended that patients on ≥20 mg of daily prednisone (or its equivalent) for ≥1 month be considered for PCP prophylaxis. 1

Couple of studies in 1990s helped define the dose and duration of corticosteroids (CS) that should prompt PCP prophylaxis. A Mayo Clinic study of patients without AIDS found that a median daily CS dose of 30 mg of prednisone or equivalent—with 25% of patients receiving as little as 16 mg of prednisone daily— was associated with PCP.2  The median duration of CS therapy before PCP was 12 weeks. A similar study found a mean CS dose of 33 mg of prednisone or equivalent with mean duration of 7 months (range 1-154 months) among patients with PCP without AIDS. 3

A 2018 retrospective study4  of patients with rheumatic diseases receiving prolonged high-dose CS therapy (≥30 mg prednisone for ≥4 weeks) found that PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) resulted in 93% reduction in the incidence of PCP with an overall number needed to treat (NNT) of 52. It was suggested that PCP prophylaxis could be discontinued in patients receiving < 15 mg of prednisone daily.

Bonus Pearl: Did you know that TMP/STX may be given either as double-strength 3x/week or single-strength daily? 5,6

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References

1. Limper AH, Knox KS, Sarosi SA, et al. An official American Thoracic Society statement: Treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med 2011;183:96-128. https://www.ncbi.nlm.nih.gov/pubmed/21193785

2. Yale SH, Limper AH. Pneumocystis carinii pneumonia in patients without acquired immunodeficiency syndrome: associated illness and prior corticosteroid therapy. Mayo Clin Proc 1996;71:5-13. https://www.sciencedirect.com/science/article/abs/pii/S0025619611649148

3. Arend SM, Kroon FP, van’t Wout JW. Pneumocystis carinii pneumonia in patients without AIDS, 1980 through 1993: An analysis of 78 cases. Arch Intern Med 1995;155:2436-2441. https://www.ncbi.nlm.nih.gov/pubmed/7503602

4. Park JW, Curtis JR, Moon J, et al. Prophylactic effect of trimethoprim-sulfamethoxazole for Pneumocystis pneumonia in patients with rheumatic diseases exposed to prolonged high-dose glucocorticoieds. Ann Rheum Dis 2018;77:664-9. https://www.ncbi.nlm.nih.gov/pubmed/29092853

5. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.http://www.pneumon.org/assets/files/789/file483_273.pdf

6. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. https://www.ncbi.nlm.nih.gov/pubmed/25269391

 

Disclosures: The listed questions and answers are solely the responsibility of the author and do not necessarily represent the official views of Mercy Hospital-St. Louis or its affiliate healthcare centers, Mass General Hospital, Harvard Medical School or its affiliated institutions. Although every effort has been made to provide accurate information, the author is far from being perfect. The reader is urged to verify the content of the material with other sources as deemed appropriate and exercise clinical judgment in the interpretation and application of the information provided herein. No responsibility for an adverse outcome or guarantees for a favorable clinical result is assumed by the author. Thank you!

 

 

When should I consider prophylaxis for Pneumocystis pneumonia (PCP) in my patient on prednisone?

Does erythrocyte sedimentation rate (ESR) have diagnostic utility in my patient with chronic renal failure?

FA Manian MD, MPH, , , , , , , , , , Leave a comment

Short answer: often not! This is because most studies have shown frequently high ESR’s in stable “uninflamed” patients with chronic renal failure (CRF) (including those on dialysis) at levels often associated with infection, connective tissue disease, or malignancy. 1-4  

In fact, in a study involving patients with CRF, 57% of patients had markedly elevated ESR (greater than 60 mm/h), with 20% having ESR greater than 100 mm/h; type or duration of dialysis had no significant effect on ESR levels.1 Another study reported a specificity for abnormal ESR of only 35% for commonly considered inflammatory conditions (eg, infections or malignancy) among patients with CRF. 2

But is it the chronic inflammation in diseased kidneys or the uremic environment that elevates ESR? A cool study compared ESR in CRF in patients who had undergone bilateral nephrectomies with those with retained kidneys and found no significant difference in the ESR between the 2 groups. 4  So it looks like it’s the uremic environment, not diseased kidneys themselves that result in elevated ESR in these patients.

The mechanism behind these observations seem to reside entirely within the patients’ plasma, not the erythrocytes. Within the plasma, fibrinogen (not gammaglobulins) seem to be the most likely factor explaining elevated ESR among patients with CRF. 1,2

Bonus pearl:  Did you know that ESR is nearly 100 years old, first described in 1921? 5

References

  1. Barthon J, Graves J, Jens P, et al. The erythrocyte sedimentation rate in end-stage renal failure. Am J Kidney Dis 1987;10: 34-40. https://www.ncbi.nlm.nih.gov/pubmed/3605082
  2. Shusterman N, Morrison G, Singer I. The erythrocyte sedimentation rate and chronic renal failure. Ann Intern Med 1986;105:801. http://annals.org/aim/fullarticle/700910
  3. Arik N, Bedir A, Gunaydin M, et al. Do erythrocyte sedimentation rate and C-reactive protein levels have diagnostic usefulness in patients with renal failure? Nephron 2000;86:224. https://www.ncbi.nlm.nih.gov/pubmed/11015011
  4. Warner DM, George CRP. Erythrocyte sedimentation rate and related factors in end-stage renal failure. Nephron 1991;57:248. https://www.karger.com/Article/PDF/186266
  5. Fahraeus R. The suspension stability of the blood. Acta Med Scan 1921;55:70-92. https://onlinelibrary.wiley.com/doi/abs/10.1111/j.0954-6820.1921.tb15200.x

 

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Does erythrocyte sedimentation rate (ESR) have diagnostic utility in my patient with chronic renal failure?

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

FA Manian MD, MPH, , , , , , , , 1 Comment

The weight of the evidence suggests that methotrexate reduces the overall risk of cardiovascular events (CVEs)—including myocardial infarction, congestive heart failure, stroke, and or major adverse cardiac events—in RA patients (RR 0.72, 95% CI 0.57-0.91)1.

Aside from its effect on controlling systemic inflammation, methotrexate has also been shown to increase HDL and reduce total cholesterol/HDL ratio in patients with RA compared with treated non-RA controls2. In vitro, methotrexate appears to activate mechanisms involved in reverse transport of cholesterol out of the cell to the circulation for eventual excretion3. Not surprisingly then, methotrexate has also been reported to decrease atherosclerotic plaque burden measured by carotid artery intima-media thickness2.

We tend to think of RA as a disease that primarily causes arthritis but its effects may extend far beyond the joints. Patients with RA have an increased risk of cardiovascular deaths compared to the general population4, likely due to a variety of factors, including accelerated atherosclerosis secondary to chronic inflammation. At baseline, RA patients also have an unfavorable lipid profile with decreased HDL and higher total cholesterol/HDL ratio.

Fun Final Fact: Did you know that methotrexate is on the WHO Model List of Essential Medicines (April 2015) not only as a cancer drug but for treatment of RA as well5?

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References:

  1. Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P, Siu S, Kraft J, Lynde C, Pope J, Gulliver W, Keeling S, Dutz J, Bessette L, Bissonnette R, Haraoui B. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2015;74:480-9. https://www.ncbi.nlm.nih.gov/pubmed/25561362
  2. Georgiadis AN, Voulgari PV, Argyropoulou MI, Alamanos Y, Elisaf M, Tselepis AD, Drosos AA. Early treatment reduces the cardiovascular risk factors in newly diagnosed rheumatoid arthritis patients. Semin Arthritis Rheum 2008;38:13-9. https://www.ncbi.nlm.nih.gov/pubmed/18191989
  3. Reiss AB, Carsons SE, Anwar K, Rao S, Edelman SD, Zhang H, Fernandez P, Cronstein BN, Chan ES. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum 2008;58:3675-83. https://www.ncbi.nlm.nih.gov/pubmed/19035488
  4. Aviña-Zubieta JA, Choi HK, Sadatsafavi M, Etminan M, Esdaile JM, Lacaille D. Risk of cardiovascular mortality in patients with rheumatoid arthritis: a meta-analysis of observational studies. Arthritis Rheum 2008; 59:1690-7. https://www.ncbi.nlm.nih.gov/pubmed/19035419
  5. WHO Model List of Essential Medicines (April 2015). http://www.who.int/medicines/publications/essentialmedicines/en/

 

Contributed by Brian Li, Medical Student, Harvard Medical School

Does methotrexate reduce the risk of cardiovascular events in patients with rheumatoid arthritis?

My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

FA Manian MD, MPH, , , , , , , , , , , , , , , Leave a comment

Night sweats (NS) is a common patient complaint, affecting about a third of hospitalized patients on medical wards1.  Despite its long list of potential causes, direct relationship between the often- cited conditions and NS is usually unclear2, its cause may remain elusive In about a third to half of cases in the primary care setting, and its prognosis, at least in those >65 y of age, does not appear to be unfavorable 2,3.

Selected commonly and less frequently cited conditions associated with NS are listed (Table)2-9.  Although tuberculosis is one of the first conditions we think of when faced with a patient with NS, it should be emphasized that NS is not common in this disease (unless advanced) and is rare among hospitalized patients as a cause of their NS1,9.

In one of the larger study of adult patients seen in primary care setting, 23% reported pure NS and an additional 18% reported night and day sweats5; the prevalence of NS in both men and women was highest in 41-55 y age group. In multivariate analyses, factors associated with pure NS in women were hot flashes and panic attacks; in men, sleep disorders. 

Table. Selected causes of night sweats

Commonly cited Less frequently cited
Neoplastic/hematologic (eg, lymphoma, leukemia, myelofibrosis)

Infections (eg, HIV, tuberculosis, endocarditis)

Endocrine (eg, ovarian failure, hyperthyroidism, orchiectomy, carcinoid tumor, diabetes mellitus [nocturnal hypoglycemia], pheochromocytoma)

Rheumatologic (eg, giant cell arteritis)

 Gastroesophageal reflux disease

B-12 deficiency

Pulmonary embolism

Drugs (eg, anti-depressants, SSRIs, donepezil [Aricept], tacatuzumab)

Sleep disturbances (eg, obstructive sleep apnea)

Panic attacks/anxiety disorder

Obesity

Hemachromatosis

Diabetes insipidus

References

  1. Lea MJ, Aber RC, Descriptive epidemiology of night sweats upon admission to a university hospital. South Med J 1985;78:1065-67.
  2. Mold JW, Holtzclaw BJ, McCarthy L. Night sweats: A systematic review of the literature. J Am Board Fam Med 2012; 25-878-893.
  3. Mold JW, Lawler F. The prognostic implications of night sweats in two cohorts of older patients. J Am Board Fam Med 2010;23:97-103.
  4. Mold JW, Holtzclaw BJ. Selective serotonin reuptake inhibitors and night sweats in a primary care population. Drugs-Real World Outcomes 2015;2:29-33.
  5. Mold JW, Mathew MK, Belgore S, et al. Prevalence of night sweats in primary care patients: An OKPRN and TAFP-Net collaborative study. J Fam Pract 2002; 31:452-56.
  6. Feher A, Muhsin SA, Maw AM. Night sweats as a prominent symptom of a patient presenting with pulmonary embolism. Case reports in Pulmonology 2015. http://dx.doi.org/10.1155/2015/841272
  7. Rehman HU. Vitamin B12 deficiency causing night sweats. Scottish Med J 2014;59:e8-11.
  8. Murday HK, Rusli FD, Blandy C, et al. Night sweats: it may be hemochromatosis. Climacteric 2016;19:406-8.
  9. Fred HL. Night sweats. Hosp Pract 1993 (Aug 15):88.
My middle age patient complains of night sweats for several months, but she has had no weight loss and does not appear ill. What could I be missing?

How should I interpret a positive result for serum cryoglobulins?

FA Manian MD, MPH, , , , , , Leave a comment

Cryoglobulins (CGs) are immunoglobulins that precipitate in the blood under cold conditions (<37◦ C) and redissolve upon warming1.  The term “cryoglobulinemia” is commonly used to describe patients with a systemic inflammatory syndrome that is often associated with small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. Although some patients with cryoglobulinemia may be asymptomatic, most present with a range of diseases characterized by fatigue, arthralgia, skin rashes or necrosis, purpura, neuropathy, bowel wall ischemia and/or glomerulonephritis and kidney failure.

Wintrobe and Buell are credited for first describing cryglobulinemia in 1933 when assessing a patient who ultimately was found to have multiple myeloma2. Since then the spectrum of diseases associated with CG has expanded to also include seemingly disparate conditions such as hepatitis C, autoimmune disorders and monoclonal gammopathy of undetermined significance (MGUS).  A commonly cited classification scheme for CG is shown (Table)3.   It should be emphasized that some CGs may not fit neatly into this scheme.

In our patient, the positive CG serum test should be interpreted in the clinical context in which it was obtained while searching for risk factors as well as signs and symptoms that may be associated with cryoglobulinemia.

 

Table. Classification of cryoglobulinemia

Category Description Examples
Type I Isolated monoclonal immunoglobulin, either IgM or IgG (less commonly IgA or free immunoglobulin light chains Multiple myeloma, Waldenström’s macroglobulinemia, monoclonal gammopathy of undetermined significance (MGUS)
Type II Mixture of monoclonal IgM and polyclonal IgG Hepatitis C, HIV, other viral infections
Type III Polyclonal mixture IgM and IgG Autoimmune disorders, hepatitis C

References

  1. Takada S, Shimizu T, Hadano Y, et al. Cryoglobulinemia (review). Mol Med Rep 2012;6:3-8
  2. Wintrobe MM, Buell MV. Hyperproteinemia associated with multiple myeloma. Bull Johns Hopkins Hosp 52: 156-165, 1933
  3. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974; 57:775-88.

 

Contributed by Kirstin Scott, Medical Student, Harvard Medical School

How should I interpret a positive result for serum cryoglobulins?

When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?

FA Manian MD, MPH, , , , Leave a comment

The most significant risk factor for PCP prophylaxis is defect in cell-mediated immunity including high-dose glucocorticoid (HDGC, ≥20 mg of prednisone daily) treatment1.  A systematic review concluded that at a PCP rate of 6.2% in control groups, PCP prophylaxis with trimethoprim/sulfamethoxazole (TMP/STX) is highly effective (85% risk reduction) in non-HIV patients with acute leukemia or solid organ/autologous bone marrow  transplantation (number needed to treat 19)2.

Other Indications for PCP prophylaxis include1:

  1. HDGC treatment for ≥1month plus another cause of immunocompromise.
  2. Combination of immunosuppressive drugs, such as tumor-necrosing factor- α inhibitors plus HDGC or other immunosuppression.
  3. Polymyositis/dermatomyositis with interstitial pulmonary fibrosis on glucocorticoids.
  4. Certain primary immunodeficiencies (eg idiopathic CD4-lymphopenia, hyper-IgM syndrome).
  5. Granulomatosis with polyangiitis (Wegener’s) on methotrexate and HDGC
  6. Rheumatologic diseases on HDGC and a second immunosuppressive drug
  7. T-cell depleting agents (eg, fludarabine)
  8. Severe malnutrition

TMP/STX may be given either as double-strength 3x/week or single-strength daily1,2.

 

References

  1. Anevlavis S, Kaltsas K, Bouros D. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV infected patients. PNEUMON 2012;25, October-December.
  2. Stern A, Green H, Paul M, Leibovici L. Prophylaxis for pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients (Review). Cochrane data of Systematic Reviews 2014, issue 10. DOI: 10.1002/14651858.CD005590.pub3. 
When should I consider Pneumocystis jirovecii pneumonia (PCP) prophylaxis in my non-HIV patient?